Systems and techniques for monitoring subjects

ABSTRACT

The present invention generally relates to systems and methods for monitoring and/or providing feedback for drugs or other pharmaceuticals taken by a subject. In one aspect, the present invention is directed to devices and methods for determining a species within the skin of a subject; and producing feedback to a subject based on the determination of the species. The feedback may be, for example, visual, audible, tactile, a change in temperature, etc. In some cases, information regarding the determination of the species may be transmitted to another entity, e.g., a health care provider, a computer, a relative, etc., which may then provide feedback to the subject in some fashion. In some cases, the feedback may be directly indicative of the species, e.g., whether the species is present, the concentration of the species, whether a by-product of a reaction involving the species is present, whether a compound affected by the species is present, etc. However, the feedback may also be indirect in some embodiments. For example, the subject may be presented with an external reward, e.g., based on the determination of the species within the skin. For instance, a reward such as cash, coupons, songs, discounts, personal items, etc., may be offered based on the level of compliance of the subject. Still other aspects of the invention are generally directed to kits involving such devices (with or without the drug to be monitored), methods of promoting such systems, or the like.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication Ser. No. 61/373,757, filed Aug. 13, 2010, entitled “Systemsand Techniques for Monitoring Subjects,” by Levinson, et al.,incorporated herein by reference.

FIELD OF INVENTION

The present invention generally relates to systems and methods formonitoring and/or providing feedback for drugs or other pharmaceuticalstaken by a subject.

BACKGROUND

One problem often faced by physicians and other health care providers isthat drugs and other pharmaceuticals that are prescribed to subjects arenot taken by the subjects, or are not taken properly by the subjects.The reasons for non-compliance or poor compliance vary, and includeforgetfulness, cost, inconvenience, lack of follow-up, and fear oftaking medications. Accordingly, techniques for monitoring or improvingcompliance are needed.

SUMMARY OF THE INVENTION

The present invention generally relates to systems and methods formonitoring and/or providing feedback for drugs or other pharmaceuticalstaken by a subject. The subject matter of the present inventioninvolves, in some cases, interrelated products, alternative solutions toa particular problem, and/or a plurality of different uses of one ormore systems and/or articles.

In one aspect, the present invention is generally directed to a device.In some embodiments, the device includes a sensor able to determine orevaluate a species (e.g., a sample of fluid, tissue, blood, etc.)withdrawn from a subject, and an indicator able to indicate an externalreward based on the determination of the species. In another set ofembodiments, the device includes means for determining a specieswithdrawn from a subject, and means for providing an external rewardbased on the determination of the species.

In accordance with some embodiments, the device includes a sensor ableto determine an amount and/or concentration of a species withdrawn froma subject, and a component able to produce non-number feedback or otherinformation related to the amount or concentration of the species.

The present invention, in another aspect, is directed to a method.According to some embodiments, the method includes acts of determining aspecies withdrawn from a subject using a device fastened to the subject,and providing an external reward based on a presence or concentration ofthe species. In another set of embodiments, the method includes acts ofdetermining a species withdrawn from a subject, on multiple days, usingone or more devices able to be fastened to the skin, and providing anexternal reward based on the number of determinations. The method, inyet another set of embodiments, includes acts of determining an amountand/or concentration of a species withdrawn from a subject using adevice fastened to the subject, and producing non-number feedbackindicative of the determination of the species.

In some embodiments, the method includes acts of determining informationrelating to a species withdrawn from a subject, transmitting theinformation to a computer, and causing the computer to provide feedbackto the subject based on the information relating to the species. Inanother set of embodiments, the method includes acts of receivinginformation obtained from a subject representing a property of a specieswithdrawn from the subject, and presenting an external reward to a userbased on the received data. The method, in still another set ofembodiments, includes acts of determining information representing aproperty of a species withdrawn from a subject using a device fastenedto the subject, and transmitting the information to a machine capable ofcausing an external reward to be presented to a user of the machine.

The method, according to one set of embodiments, includes acts ofadministering a drug to a subject, determining a species withdrawn froma subject that is indicative of the drug administered to the subject,and providing feedback to the subject regarding the species. In someembodiments, the drug administered to the subject is not distinguishablefrom a placebo by the subject without any external equipment.

In yet another set of embodiments, the method includes acts ofadministering a drug to a subject having a condition suspected of beingtreatable by the drug, determining a species withdrawn from a subjectthat is indicative of the drug administered to the subject, andproviding feedback to the subject regarding the species. In some cases,the drug does not cause a measurable change to the condition of thesubject within the first 24 hours after administering the drug.

In one aspect, the present invention is generally directed to adevice-implemented method. In some embodiments, the method includes actsof applying a device to a subject, where the device is able to obtain aphysical measurement from the subject, and based on obtaining themeasurement, effecting a financial transaction with the device.

The method, in certain embodiments, includes acts of applying a deviceto a subject, wherein the device is able to obtain an invasive physicalmeasurement from the subject, and based on obtaining the measurement,recommending a medical treatment with the device.

In certain embodiments, the method includes acts of applying a device toa subject, where the device is able to obtain an invasive physicalmeasurement from the subject, and based on obtaining the measurement,performing a medical treatment on the subject using the device.

According to some embodiments, the method includes acts of applying adevice to a subject, where the device is able to obtain an invasivephysical measurement from the subject, and based on obtaining themeasurement, delivering a drug to the subject using the device.

The method, in some embodiments, includes acts of receiving medical datafrom a subject in a device, determining positional data of the subjectin the device, and producing composite data comprising the medical dataand the positional data using the device.

The method, in yet other embodiments, includes acts of determining aspecies withdrawn from a subject using a device fastened to the subject,and providing an external reward to a person other than the subjectbased on a concentration of the species.

In some embodiments, the method includes acts of injecting a tracer intoa subject using a device comprising a plurality of microneedles, andtracking movement of the subject by remote monitoring of the tracer.

In certain embodiments, the method includes acts of injecting apopulation of subjects with tracers using devices each comprisingmicroneedles, and determining a characteristic of the population ofsubjects by determining the tracers within the population of subjects.

In another aspect, the present invention is generally directed to adevice. According to certain embodiments, the device includes a fluidtransporter able to withdraw fluid from a subject, a sensor able todetermine an analyte suspected of being present within the withdrawnfluid and configured to receive the withdrawn fluid, and a transmitterresponsive to the sensor and able to effect a financial transaction as afunction of the sensor's determination.

The device, according to some embodiments, includes a fluid transporterable to withdraw fluid from a subject, a sensor able to determine ananalyte suspected of being present within the fluid, a processor able todetermine a drug treatment based at least in part on the sensordetermination, and a reservoir for containing a drug deliverable to thesubject based on the processor determination.

In accordance with some embodiments, the device includes a sensor ableto determine a species withdrawn from a subject, and a device indicatorable to indicate an external reward based on the determination of thespecies.

In another aspect, the present invention encompasses methods of makingone or more of the embodiments described herein. In another aspect, thepresent invention encompasses methods of using one or more of theembodiments described herein.

Other advantages and novel features of the present invention will becomeapparent from the following detailed description of various non-limitingembodiments of the invention when considered in conjunction with theaccompanying figures. In cases where the present specification and adocument incorporated by reference include conflicting and/orinconsistent disclosure, the present specification shall control. If twoor more documents incorporated by reference include conflicting and/orinconsistent disclosure with respect to each other, then the documenthaving the later effective date shall control.

BRIEF DESCRIPTION OF THE DRAWINGS

Non-limiting embodiments of the present invention will be described byway of example with reference to the accompanying figures, which areschematic and are not intended to be drawn to scale. In the figures,each identical or nearly identical component illustrated is typicallyrepresented by a single numeral. For purposes of clarity, not everycomponent is labeled in every figure, nor is every component of eachembodiment of the invention shown where illustration is not necessary toallow those of ordinary skill in the art to understand the invention. Inthe figures:

FIG. 1A-1B illustrate devices according to certain embodiments of theinvention;

FIGS. 2A-2C illustrate devices according to various embodiments of theinvention;

FIG. 2D illustrates a kit containing more than one device, in yetanother embodiment of the invention;

FIG. 2E illustrates a device according to still another embodiment ofthe invention;

FIGS. 3A-3C illustrate certain methods in accordance with variousembodiments of the invention;

FIG. 4 is a schematic diagram illustrating a device transmittinginformation about a species from a subject to a device able to offer areward, in accordance with one embodiment of the invention; and

FIGS. 5A-5D illustrate various methods, in accordance with certainembodiments of the invention.

DETAILED DESCRIPTION

The present invention generally relates to systems and methods formonitoring and/or providing feedback for drugs or other pharmaceuticalstaken by a subject. In certain embodiments, feedback to the subject, orto other personnel, may take the form of visual and/or audible displays,or financial rewards or incentives. Examples include coupons,memberships, cash, or the like. Some embodiments are generally directedto devices for monitoring a subject, and in some cases, engaging infinancial transactions related to the condition of the subject, forexample, transmitting insurance claims, charging a financial account,recording payments, or the like. In certain embodiments, the monitoringmay take the form of medical monitoring. For example, in response to acondition of the subject, a device may transmit or display data orinformation relating to the condition of the subject to the subject,and/or to other personnel such as relatives, friends, or medicalpersonnel, who could then take appropriate actions depending on thecondition of the subject. In some cases, the device itself may also beable to perform medical treatments, for example, by delivering a drug orother pharmaceutical agent to the subject, e.g., such as is describedherein. For example, the device may be able to deliver a hormone, aprotein, a small molecule, etc., to the subject, and/or the device maybegin monitoring other analytes within the blood (or other fluid). Insome cases, the device may be used to deliver an electric charge orshock to the subject as part of the medical treatment. In some cases,the device may also transmit other data concerning the subject, forexample, the location of the subject, or vital factors relating to thesubject (e.g., the subject's temperature or blood pressure).

Some embodiments of the invention are directed to populations ofindividuals, e.g., where a population of individuals is tracked todetermine a condition of the population. For example, blood from apopulation of individuals may be obtained using various devices such asthose described herein, and data based on the blood samples may be used,for example, to track the spread of a disease. In some cases, suchsamples may be obtained without knowledge by the individuals. Thus, incertain embodiments, one or more individuals may be tracked covertly.For example, an individual may be tracked to determine his or herlocation, for instance, by obtaining a blood sample from the individual,and/or by injecting a tracer in the individual that can be laterdetected (e.g., remotely, or using a covertly obtained blood sample fromthat individual). Thus, for instance, the location of an individual maybe determined by studying an analyte within the blood that is indicativeof the location of the individual, or tracers may be covertly applied atone location to individuals at that location to determine if the subjectin question had been through that location. Examples of these arediscussed in detail below.

In one aspect, the present invention is directed to devices and methodsfor determining a species within the skin of a subject, and producingfeedback to a subject based on the determination of the species. Thefeedback may be, for example, visual, audible, tactile, a change intemperature, etc. In some cases, information regarding the determinationof the species may be transmitted to another entity, e.g., a health careprovider, a computer, a relative, etc., which may then provide feedbackto the subject in some fashion. In some cases, the feedback may bedirectly indicative of the species, e.g., whether the species ispresent, the concentration of the species, whether a by-product of areaction involving the species is present, whether a compound affectedby the species is present, etc. However, the feedback may also beindirect in some embodiments. For example, the subject may be presentedwith an external reward, e.g., based on the determination of the specieswithin the skin. For instance, a reward such as cash, coupons, songs,discounts, personal items, etc., may be offered based on the level ofcompliance of the subject. Still other aspects of the invention aregenerally directed to kits involving such devices (with or without thedrug to be monitored), methods of promoting such systems, or the like.

In one aspect, the present invention is generally directed to devicesable to monitor or provide feedback to a subject taking a drug or otherpharmaceutical, and/or to other personnel. For example, feedback may beprovided to a relative of the subject, a caregiver for the subject,medical personnel caring for the subject (e.g., a nurse, a doctor,etc.), or the like. Thus, in certain embodiments, feedback may beprovided to anyone who would communicate such feedback to the subject.The feedback given to the subject may be based on information regardingthe determination of the drug or other pharmaceutical, for example, anamount and/or concentration of the drug or other pharmaceutical withinthe subject. For instance, the feedback may include informationregarding the subject's compliance with taking one or more drugs orother pharmaceutical compositions. Depending on the personnel,additional information may be given to the subject, e.g., warnings aboutcompliance (or lack thereof), information about potential druginteractions, suggestions for improving compliance, suggestions forchanges in lifestyle, or the like.

The species to be determined within the subject may be present anywherewithin the subject, e.g., within the skin of the subject, and/or withinother bodily fluids such as blood or interstitial fluid. The species maybe an administered composition (e.g., a drug or other pharmaceutical),and/or another species that is related to the composition, such as atracer or other compound taken with the administered compound, forexample, such as the systems and methods disclosed in U.S. Pat. Apl.Ser. No. 61/163,733, filed Mar. 26, 2009, entitled “Determination ofTracers within Subjects,” by Douglas A. Levinson (incorporated byreference herein in its entirety). For example, the species to bedetermined may be the product of an interaction of the drug (or otherpharmaceutical) with the subject. As specific non-limiting examples, thespecies may be a metabolite of the administered composition, a productor by-product of the administered composition with the subject (forexample, a cleavage product), a marker for a disease that is treatableby the administered composition (for instance, a protein, a hormone, asmall molecule, etc.), a species within the body that the administeredcomposition interacts with (e.g., degrades), such as a target of theadministered composition (for example, a protein or enzymatic targetwithin the subject), or the like. Accordingly, in the descriptionherein, it should be understood that references to determining the drug(or other pharmaceutical or other administered composition) in thesubject (e.g., in the skin, blood, interstitial fluid, etc. of thesubject) are by way of example only, and in other embodiments, otherspecies related to the administered composition may be determined in anysuitable location within the subject, instead of or in addition to theadministered composition, such as those described herein.

In certain embodiments, the device is able to interrogate a portion of asubject, for example, a blood sample taken from the subject, and inresponse, initiate or effect a financial transaction, or recommend orperform a medical treatment on the subject. In some cases, theinterrogation is invasive. For instance, the interrogation may involvethe insertion of an object into a subject, and/or the receiving of asubstance (such as blood) from the subject. In contrast, measurementssuch as measuring temperature or blood pressure are not invasive sincethere is no insertion and/or receiving of a substance into or out of theskin (or beneath the skin) of the subject.

For example, the financial transaction may be performed directly by thedevice, and/or the device may interface with another device able toperform the financial transaction. The financial transaction may beassociated with the actions taken by the device, and/or based on ananalyte determined by the device. For example, a financial transactionmay occur every time the device is used (e.g., every time the devicedelivers and/or receives a substance to or from the subject), every timea drug is delivered by the device, every time an assay is performed bythe device, on a regular basis (e.g., akin to rent), or the like. Thefinancial transaction may be a charge to a credit card, a charge card, acredit account, a bank account, a debit account, an insurance account,or the like. In some embodiments, the device may cause an insuranceclaim or a claim against the government (e.g., for social security,Medicare, Medicaid, etc.) to be entered.

In some embodiments, the device comprises a transmitter able to conducta financial transaction. For example, the transmitter may be able toaccess a wireless system to conduct the financial transaction, e.g.,using established procedures, or the device may be plugged into atransmitter in order to process the financial transaction. The devicemay also contain a processor for recommending and/or for performing amedical treatment. In some cases, the processor may include a database,e.g., of drug information and/or other kinds of suitable medicaltreatment. For instance, the processor may be able to determine, via oneor more sensors, an analyte suspected of being present in blood or otherfluid received from a subject, and based on the analyte, take someaction, for example, sending a signal (e.g., to the subject or otherpersonnel, e.g., to a doctor), or in some cases, activating an actuator,e.g., for delivering a drug or other pharmaceutical to the subject. Asan example, the device may inject a drug into the subject using one ormore microneedles or other fluid transporters or substance transfercomponents, based on sensor readings of a fluid such as blood receivedfrom the subject.

A non-limiting example of such a process is now described with respectto the flowchart shown in FIG. 5A. In this figure, a device is appliedto a subject 521, e.g., by the subject (i.e., self-administered) oranother person (e.g., a health care provider). The device is thenactivated (or in some cases, self-activated) to withdraw or receivefluid or other sample 522 from the subject, e.g., blood, interstitialfluid, etc. The device may then analyze the fluid to determine one ormore species 523, e.g., using one or more sensors as discussed herein.In some cases, analysis of the species occurs on the device itself.Based on this determination, the device may effect a financialtransaction 524. For example, the financial transaction may includetransmitting insurance claims, charging a financial account, recordingpayments, or the like. The financial transaction may also include acharge to a credit card, a charge card, a credit account, a bankaccount, a debit account, an insurance account, or the like. In someembodiments, the financial transaction may be an insurance claim or aclaim against the government. Other suitable financial transactions arediscussed herein.

A non-limiting example of a process for recommending a medical treatmentis shown in the flowchart in FIG. 5B In this figure, a device is appliedto a subject 531, e.g., by the subject (i.e., self-administered) oranother person (e.g., a health care provider). The device is thenactivated (or in some cases, self-activated) to withdraw or receivefluid or other sample 532 from the subject, e.g., blood, interstitialfluid, etc. The device may then analyze the fluid to determine one ormore species 533, e.g., using one or more sensors as discussed herein.In some cases, analysis of the species occurs on the device itself.Based on this determination, the device may recommend a medicaltreatment. For example, the device may include a database of potentialtreatments, and determination of the species from 533 may be used toselect a suitable medical treatment, e.g., for display by the device,and/or for by display by an output device, for instance, output device51 in FIG. 4. For instance, the medical treatment may be to continuetaking a drug or other pharmaceutical agent (or to stop taking the drugor other pharmaceutical), to increase or decrease the dosage of the drugor other pharmaceutical, to take another drug or other pharmaceuticalagent, to avoid taking certain drugs or other pharmaceutical agents(e.g., in the case of adverse drug interactions), to eat or avoid eatingcertain foods (e.g., containing sugar, or foods implicated in allergicreactions), to rest or sleep, to see a doctor or other medicalpersonnel, etc. FIG. 5C is a similar example flowchart, except thedevice may be able to perform a suitable medical treatment in 535, e.g.,by delivering a drug or other pharmaceutical agent to the subject.

Feedback from the device may be provided in any suitable form. Asmentioned, feedback may be provided to the subject, or to otherpersonnel. In some cases, the feedback may be directly provided by thedevice, e.g., to the subject after determination of the species. Incertain embodiments, the feedback may be auditory, visual, olfactory,tactile, thermal, or the like.

For example, if the feedback is auditory, the feedback may includesounds such as jingles, songs, music, sound effects, or the like. Insome cases, the sounds may be selectable by the subject or otherpersonnel. For instance, the subject may select a first song indicatingcompliance, and a second song (or no song) indicating non-compliance;the subject may also select additional songs in some embodiments forother indications (e.g., partial compliance, a reminder to take thecomposition, a song indicating successful compliance over somepredetermined period of time or number of administrations, etc.). Soundmay be produced by a device using any suitable technique, for example,using a speaker or a relay clicker. Techniques for causing a speaker toplay music or sounds will be familiar to those of ordinary skill in theart. For example, the speaker may be a digital speaker that plays songsstored in a memory device, e.g., in any suitable format (e.g., flashmemory, magnetic tape, hard drive memory, optical media such as CDs orDVDs, or the like). Other types of sounds may be used in otherembodiments, for example, sound effects (e.g., beeps, buzzes, jingles,etc.), synthesized sounds or speech, verbal reminders, or the like.

As another example, the feedback may be tactile or temperature (e.g.,such that the subject senses a change in temperature of the device). Onenon-limiting example of a tactile sensation is a change in temperature(e.g., getting warmer or cooler), for example, using electronic heatingor cooling devices such as resistive heaters or Peltier coolers. Thus,as a particular example, a device may be worn that produces heat orcooling when compliance is lacking, thereby reminding the wearer toadminister the drug or other pharmaceutical. As other examples oftactile feedback, the device may vibrate, tighten or loosen, etc. toindicate certain conditions. For instance, the device may be worn aroundthe arm (e.g., as in a bracelet or wristwatch), and the device maytighten around the arm if the subject has not been compliant.

In some embodiments, the feedback may be visual. For example, the devicemay include one or more lights, LEDs, LCDs, a screen able to display animage, or the like. As a specific non-limiting example, lights may beprovided that are red when compliance is lacking and green if thesubject exhibits adequate compliance. In some cases, the lights may alsoflash, e.g., to get attention. Other lights may be provide in otherembodiments, for example, to indicate that the next administration isdue, to indicate operation of the device, to indicate successfulcompliance over some predetermined period of time or number ofadministrations, etc. As another example, a light within the device maybe used to produce a logo or an advertisement when the composition hasbeen taken, etc. In some cases, the feedback may be non-number based,i.e., the feedback does not include the display of numbers, but insteadcontains other methods or symbols to indicate feedback, e.g., lights,bars, plots, signals, graphs, logos, or the like. As still anotherexample, the device may display numbers, a series of lights, pictograms,LEDs, LCDs, logos, etc., indicating information regarding the specieswithin the subject, for example, the concentration, the number of timesthe drug or other pharmaceutical was taken by the subject, the timesince the last administration of the drug or other pharmaceutical waspreviously administered, the time before the next administration, or thelike. If a screen is used, the screen may be able to display arbitraryinformation, e.g., regarding operation of the device, informationregarding the species within the subject, information regardingadministration of the drug or other pharmaceutical, weblinks, or otheruseful information, etc. In still another embodiments, the device mayproduce a desirable display of lights, logos, advertisements, movies,etc., as a reward for successful compliance.

These may also be combined in still other embodiments. For example, thedevice may produce a movie with sounds to indicate compliance (or lackthereof), the device may produce blinking lights during or following asong, or the like.

In certain embodiments, the feedback that is provided by the device maybe related to the drug or other pharmaceutical in some way. For example,the feedback may indicate whether the drug (or other pharmaceutical) wastaken or not, the degree of compliance, the concentration of a specieswithin the subject (measured directly or indirectly, e.g., bydetermining a metabolite within the subject), the time since the drugwas taken, the time until the next administration of the drug, thenumber of administrations, etc. In some of embodiments, the feedback maybe a reward indicating some degree of successful compliance. Forexample, feedback may be provided after the subject has taken the drug,after the subject has taken the drug a certain number of times, afterthe subject has taken the drug for a certain period of time, once acertain concentration of a species within subject has been reached, orthe like. The feedback may be numerical and/or non-numerical. Suchfeedback may, in some embodiments, be of sufficient value to the subjectthat the subject may behave in a certain way, e.g., increasingcompliance or continuing taking the drug or other pharmaceutical. Inother embodiments, as discussed herein, the feedback may include areward, such as an external reward. The reward may also influence thesubject's behavior in some cases.

In some cases, feedback may be provided to the subject in real time,e.g., by the use of a graph, numbers, lights, etc. As a particularexample, the device may display a number that indicates theconcentration of a species within the subject (e.g., glucose), andoptionally, when a certain concentration is reached, the device may alsoindicate to the subject in some fashion that a medication (e.g.,insulin) is needed, for example, by activating a light, displaying alogo, playing a sound or a song, or the like.

The device may be used once, or multiple times. For instance, in someembodiments, the device may be used to determine a species within theskin at multiple points of time, e.g., on multiple days, or evencontinuously in some instances. Feedback may be provided to the subjectimmediately or within a short time after determining the species, and/orinformation regarding the species may be stored for later use (e.g., asdiscussed below). For instance, in certain embodiments, after thesubject has taken the drug a certain number of times, or after a certainnumber of days, feedback may be provided to the subject, for example, inthe form of a reward as discussed below.

As discussed, in some embodiments, feedback is provided by the deviceitself. However, in other embodiments, feedback may be provided byanother entity. The entity may be another person (such as a relative,medical personnel, etc.), or a non-living entity, such as a computer oran Internet-based service. For example, information about the speciesmay be transmitted to the other entity, which may then provide feedbackto the subject in a suitable fashion.

In some embodiments, the device may transmit information regarding thesubject and/or administration of the drug or other pharmaceutical toanother entity. The information may be transmitted, e.g., wirelessly(for example, using radio antennas, transceivers, infrared light, laserlight, visible light, acoustic energy, or the like), or through the useof wires (for example, using electronic ports such as parallel ports,serial ports, USB connections, RS232/485 communication transceivers,4-20 mA analog transceivers, an Ethernet transceiver, or the like). Anysuitable transmission protocol may be used, e.g., Bluetooth, Wi-Fi orIEEE 802.11, WiMax, peer-to-peer networking, Wireless FireWire, or thelike. The information may be transmitted relatively quickly afterdetermination of a species within the subject, and/or the informationmay be stored for later transmission and/or retrieval, for example, bythe subject, or by another person.

If information is stored on the device, any suitable technique may beused to store such information, e.g., in a data storage compartment, forexample, silicon integrated circuits, magnetic media, optical media, orother kinds of data storage devices. In one embodiment, the data storagecomponent includes a computer-readable medium, for example, a mediumthat stores information through electronic properties, magneticproperties, optical properties, etc. of the medium. Examples ofcomputer-readable media include, but are not limited to, silicon andother semiconductor microchips or integrated circuits, radio frequencytags or circuits, compact discs (e.g., in CD-R or CD-RW formats),digital versatile discs (e.g., in DVD+R, DVD-R, DVD+RW, or DVD-RWformats), insertable memory devices (e.g., memory cards, memory chips,memory sticks, memory plugs, etc.), “flash” memory, magnetic media(e.g., magnetic strips, magnetic tape, DATs, tape cartridges, etc.),floppy disks (e.g., 5.25 inch or 90 mm (3.5 inch) disks), optical disks,and the like. In some embodiments, the data storage component may bereversibly attached to and removed from the device. In some embodiments,the data storage component may be volatile, i.e., some power is requiredby the data storage component to maintain the data therein. In otherembodiments, however, the data storage component is non-volatile. Insome embodiments, the data storage component is an element that isconstructed and arranged to allow data to be stored to and/or retrieved.In one embodiment, the memory or data storage component includes a datastorage chip. As used herein, a “data storage chip” is a microchip ormicroprocessor to which data can be stored and/or retrieved. Typically,the data storage chip comprises a semiconductor and often containselectronic circuitry. In some cases, the data may include drug treatmentdata, medical treatment data, etc.

In some embodiments, information regarding the subject and/oradministration of the drug or other pharmaceutical may be delivered tothe subject or another person. For instance, the device may determine aspecies within the skin of a subject, then transmit the informationregarding the species to another entity, e.g., a receiver, a computer, aweb page on the Internet, etc., for retrieval and/or analysis by anotherperson, e.g., the subject, a relative, medical personnel, etc. Ifanother person is involved, the person may provide feedback to thesubject. For example, the person could review information regarding thespecies, and/or make a determination regarding compliance of the subjectwith administration of the drug or other pharmaceutical. In some cases,the person may give advice (such as medical advice), warnings,encouragement, counseling, etc., to the subject regarding administrationand/or compliance issues. In addition, as previously discussed, in someembodiments, additional information may also be given to the subject,for example, information about potential drug interactions, suggestionsfor changes in lifestyle, methods for improving compliance, changes inprescription, or the like.

In some cases, the information may be combined with other information ordata. For instance, information regarding the subject, e.g., regardingconcentration of a species within the subject, and/or other medicalinformation about the subject (e.g., the subject's temperature, bloodpressure, oxygen levels, etc.) may be combined with other data, forexample, indicating the time of day, the location of the subject, or thelike. For instance, in certain embodiments, the location of the subjectmay be determined using GPS (“Global Positioning System”) receptionequipment, or other similar systems (e.g., Galileo, Beidou, COMPASS,GLONASS, IRNSS, QZSS, etc.). In some cases, a device may include asuitable receiver (e.g., a GPS receiver), and/or the device may be ableto electronically interface with a separate receiver, e.g., one carriedby the subject. Many types of receivers, e.g., for GPS, can be obtainedcommercially. The data may be combined to produce composite data thatcan be, for example, stored in memory, transmitted to another entity,displayed on a web page, or the like, e.g., as is described herein. Anexample is illustrated in the flowchart of FIG. 5D, where positionaldata 511 and medical data 512 are combined to produce composite data513.

Thus, in some embodiments, the same device may be used to determine bothpositional data and medical data regarding the subject. In otherembodiments, however, more than one device may be used. For example, afirst device may determine medical data and a second device maydetermine positional data, then the data combined to produce thecomposite data (e.g., comprising at least the medical data and thepositional data), either in the first device, the second device, or insome cases, in a third device.

In some embodiments, the device may indicate that the subject (oranother person, as described herein) may have access to a web page. Thedevice may have a device indicator that indicates access to the web pageby any suitable technique, for example, visual, audible, tactile, achange in temperature, etc. As non-limiting examples, the device mayturn on a light, display an image or a logo, to produce a sound, play asong, etc. to indicate that the web page is accessible, to indicate achange or an update in the content of the web page, produce a reminderto review the web page, etc.

The web page may be used to display information to the subject, and/orto another person. For instance, in certain embodiments, the device maytransmit information to another entity (e.g., a computer), and thecomputer may produce a web page that can be accessed by the subject, oranother person. In some cases, the web page may be a private orencrypted web page accessible only to the subject, and/or only to selectindividuals (e.g., certain doctors or other health care providers). Theweb page may display information relating to the species, otherinformation of interest to or for the subject, or in some cases, the webpage may be used to provide a reward to the subject, e.g., forsufficient compliance.

For example, the web page may, in some embodiments, display informationrelating, directly or indirectly, to the species. For example, the webpage may display information regarding compliance or administration ofthe drug or other pharmaceutical by the subject, the concentration of aspecies in the subject (e.g., of the drug or other pharmaceutical, or aspecies related to the drug or other pharmaceutical, e.g., a metabolite,a target, a product, a by-product, a marker for a disease treatable bythe drug or other pharmaceutical, etc.). As other examples, the web pagemay indicate whether the drug (or other pharmaceutical) was taken ornot, the number of times it was taken by the subject, the degree ofcompliance, the concentration of a species within the subject (measureddirectly or indirectly, e.g., by determining a metabolite within thesubject), the time since the drug was taken, the time until the nextadministration of the drug, the number of administrations, otherhealth-related information (e.g., relating to the composition, forexample, potential side effects, allergic reactions, interactions withother drugs, etc.), as well as past histories or one or more of these insome cases, or the like.

In some cases, the web page may display information of interest to orfor the subject. As non-limiting examples, the web page may displayinformation or advertising regarding the drug or other drugs ofpotential interest to or for the subject, health-related information,links to related web sites, or the like. As specific examples, the webpage may include a link to an on-line “chat” with medical personnel whocan answer questions that the subject may have regarding the subject'shealth, or the web page may provide counseling regarding improvingcompliance of the subject in taking the drug or other pharmaceutical.

In some embodiments, the web page may use information relating to thespecies to produce information, data, probabilities, etc., relating tothe subject. For instance, the web page may indicate that, bysuccessfully complying with a treatment for a certain period of time,the probability of an adverse event has been changed. As a specificexample, the web page may report that, by successfully complying withtreatment over a certain period of time, the probability of a heartattack has decreased by a certain percentage, the probability of anacute attack of a disease has decreased by a certain percentage, thelife expectancy of the subject has increased by a certain amount, etc.

According to some embodiments, feedback provided to the subject mayinclude a reward, e.g., upon achieving some level of successfulcompliance. For example, the feedback or reward may be provided afterthe subject has taken a drug (or other pharmaceutical), after thesubject has taken the drug a certain number of times, after the subjecthas taken the drug for or after a certain period of time, once a certainconcentration of a species within subject has been reached, or the like.In some cases, the reward may be one selected by the user; in othercases, the reward may be determined by another person, e.g., by a doctoror other health care provider, or the reward may be predetermined. Forinstance, as discussed below, in certain embodiments, a kit may beprovided to the subject that includes a drug or other pharmaceutical,and a device able to determine the drug within the skin. The device may,in some cases, be preprogrammed to give a reward when a certaincompliance by the subject is reached.

The reward may be any suitable reward. In some cases, the reward may beone determinable by the user. In some embodiments, the reward may beprovided directly by the device. For instance, the device may display animage, play a song or music, display a pattern of lights, play a movieor a movie clip, etc., as a suitable reward to the subject. In somecases, however, the reward may be one that is external to the device,i.e., the reward is an “external reward.” For example, the reward may bea monetary reward (e.g., cash, coupons, discounts, gift cards, etc.),physical merchandise (e.g., of a predetermined nature, or selectable bythe user, etc.), downloadable content (e.g., sound files, game files,pictures, movies, etc.), or the like. As a specific non-limitingexample, the reward may be one or more arbitrary “points,” and when acertain number of points are reached, the subject may be given a reward,or the subject may be allowed to choose a reward from a number ofpotential rewards. In some cases, the subject may be able to acquireeven more points (for example, for higher levels of compliance, longerperiods of compliance, smaller fluctuations in the concentration of aspecies, etc.) and the ability to choose even larger or more valuablerewards. The reward may be selectable, for example, by access to asuitable web page (e.g., as discussed herein), by selecting an item froma physical or an electronic catalog, or the like.

Examples of coupons include, for instance, coupons to restaurants,hotels, cars, vacations, health clubs, or the like. Other examples ofmonetary or financial rewards include, but are not limited to, increasedpay, discounts for prescriptions, memberships to health clubs, drugdiscount programs, loyalty cards, gift cards, changes in insurancepremiums, or increased time off (e.g., increased vacation days), or thelike. As additional examples, the external reward may take the form ofe-mail or other electronic messages sent to the subject (or otherentity), or electronic short messages such as Twitter posts or tweets.The messages may be in the form of congratulatory messages, statusupdates, encouragement, weblinks, or the like.

As previously discussed, feedback may be provided to the subject, or topersons other than the subject, for example, to a relative of thesubject, a caregiver for the subject, medical personnel caring for thesubject (e.g., a nurse, a doctor, etc.), or the like. The feedback mayalso include, for example, monetary or financial rewards (e.g.,“kickbacks” for successful performance by the subject, changes in pay,bonuses, or the like).

In one aspect, the present invention is directed generally to devicesable to monitor or provide feedback to a subject taking (or not taking)a drug or other pharmaceutical substance, and/or to provide suchfeedback to other personnel. For example, feedback may be provided to arelative of the subject, a caregiver for the subject, medical personnelcaring for the subject (e.g., a nurse, a doctor, etc.), or the like.Thus, in one set of embodiments, feedback may be provided to anyone whowould communicate such feedback to the subject. The subject is typicallyhuman, although the subject may be non-human in some cases. The feedbackgiven to the subject may be based on information regarding thedetermination of the drug or other pharmaceutical substance, forexample, an amount and/or concentration of the drug or otherpharmaceutical substance within the subject. The determination may bequalitative (e.g., determining the presence or absence of the drug orother pharmaceutical substance) and/or quantitative (e.g., determiningan amount and/or concentration, etc.). For instance, the feedback mayinclude information regarding the subject's compliance with taking (ornot taking) one or more drugs or other pharmaceutical substances.Depending on the personnel, additional information may be given to thesubject, e.g., warnings about compliance (or lack thereof), informationabout potential drug interactions, suggestions for improving compliance,suggestions for changes in lifestyle, or the like.

A non-limiting example of such a process is now described with respectto the flowchart shown in FIG. 3A. In this figure, a device is appliedto a subject 321, e.g., by the subject (i.e., self-administered) oranother person (e.g., a health care provider). The device is thenactivated (or in some cases, self-activated) to withdraw or receivefluid 322 from the subject, e.g., blood, interstitial fluid, etc. Thedevice may then analyze the fluid for one or more species, e.g., usingone or more sensors as discussed herein. In some cases, analysis of thespecies occurs on the device itself. In certain instances, informationabout the species (e.g., the presence and/or absence, concentration,amount, etc.) is transmitted externally of the device, e.g., to acomputing device, which may also in some embodiments return a signal tothe device. After such analysis, if certain conditions are met, thedevice may activate an indicator 323 (e.g., light, sound, graphics,music, etc.) which alerts the subject (or another person) that anexternal reward or punishment is available. The subject (or anotherperson) can then access a computing device 324 (which may be the same ordifferent from the computing device discussed above) to access theexternal reward and/or to determine what punishment is to be applied.The computing device may, for example, display a weblink to access thereward or punishment, and/or there may be an output device able tooutput a reward (e.g., a coupon or a certificate).

As illustrated in the non-limiting example of FIG. 3B, the device, inone set of embodiments, may be operated as follows. A sample may bewithdrawn or received from a subject to which the device is applied 331.For example, the sample may be blood, interstitial fluid, or the like.The device then analyzes the sample 332 to determine one or more specieswithin the sample, e.g., the presence and/or absence, amount,concentration, etc. For example, one or more sensors as discussed hereinmay be present within the device. In some cases, analysis of the speciesoccurs on the device itself. In certain instances, the device interfaceswith an external computing device 333 so that information about thespecies (e.g., the presence and/or absence, concentration, amount, etc.)can be transmitted externally of the device, e.g., to a computingdevice, which may also in some embodiments return a signal to thedevice. Based on such analysis, the device may then activate anindicator 334, for example, light, sound, graphics, music, etc. to alertthe subject (or another person) that an external reward (or punishment)is available. In some cases, the device itself may perform the analysisof the species and activate the indicator, prior to interfacing with anexternal computing device.

One non-limiting example method of using the computing device is nowillustrated with respect to FIG. 3C. In this figure, an externalcomputing device (e.g., a general purpose computer, a specially-builtcomputer, an application-specific integrated circuit, a microprocessor,etc.) receives a transmission 351 from a device that is used to withdrawor receive a sample from a subject for analysis. The sample may be, forexample, blood or interstitial fluid. For example, the device mayinclude one or more sensors able to determine a species suspected ofbeing present within the sample withdrawn or received from the subject,and the device may transmit sensor data, and/or the device may analyzesensor data and transmit information about the species (e.g., thepresence or absence, amount, concentration, etc.) to the computingdevice. In this example, based on the transmission, the computing devicemay determine if a reward (or punishment) is appropriate 352, e.g.,using criteria such as those described herein. Optionally, the computingdevice (or another computing device) may be used by the subject, oranother person, to access an external reward or punishment 353. Forexample, the computing device may be a computer that a person can loginto to receive the external reward. In some cases, the computer devicemay be connected to an output device for producing the external reward,e.g., a screen, a TV, a printer, a speaker, or the like.

A schematic illustration of another example system is shown in FIG. 4.In this figure, a device 44 for withdrawing or receiving a fluid isplaced on a portion of a subject 41 (e.g., an arm or a leg), and in somecases, immobilized thereto (for example, using an adhesive). Afterwithdrawing or receiving a sample from the subject (e.g., blood orinterstitial fluid), device 44 determines one or more species suspectedof being present within the sample using one or more sensors.Information from the sensors may be analyzed by device 44, and/ortransmitted 48 to an external computing device 47. For example, device44 may determine the presence of a species, and in some cases, determineif an external reward (or punishment) should be offered to the subject.If an external computing device is used, any method of transmission tothe computing device may be used, including wireless or radiotransmissions. In some embodiments, device 44 may also be able todetermine positional data, e.g., if device 44 includes a GPS receiver,which may also be transmitted to external computing device 47.

In some cases, external computing device 47 may also send a signal backto device 44. For example, in some embodiments, external computingdevice 47 may be used to analyze the species and determine if anexternal reward (or punishment) should be offered to the subject. Thus,information about the species and/or whether such an external reward orpunishment should be offered may be transmitted back to device 44.

If it is determined that the subject should be offered an externalreward (or punishment), device 44 may activate a suitable indicator 43to inform the subject (or another person). For example, indicator 43 maybe include a display screen, a speaker, a light or an LED, or the like,e.g., as discussed herein. Computing device 47, and/or another outputdevice 51, may then be used to offer the external reward (or punishment)to the subject (or other person). For example, the subject or otherperson may access computing device 47 and/or output device 51 to claimthe reward or accept the punishment.

In some aspects, the systems described herein may be useful for anydrug. In some cases, the drug may be one in which the benefit to thesubject taking the drug is not necessarily immediate or apparent. Forexample, a drug able to treat anemia or decrease cholesterol levels mayhave benefits that are not immediately felt by the subject (e.g., anincrease in red blood cell count or a decrease in the amount ofcholesterol found in the blood). Thus, the subject taking the drug maynot be aware of any immediate substantial benefit by taking the drug. Inmany cases, the subject is discouraged from taking the drug due to thelack of any positive feedback, i.e., beneficial effects, by taking thedrug. In some instances, this may be compounded by drugs having one ormore adverse side effects, i.e., the subject is immediately exposed toadverse side effects upon taking the drug, while the beneficial effectsof taking the drug are not immediately apparent. Accordingly, it is afeature of certain embodiments of the invention to provide feedbacksystems for subjects taking drugs, including but not limited to drugshaving benefits that are not necessarily immediate or apparent.

In some embodiments, the drug is one whose beneficial effects occur onthe time scale of weeks, or drugs whose main actions do not occur untilat least about a day. Examples of such drugs include, but are notlimited to, drugs that treat anemia, drugs that lower cholesterol, ordrugs that treat high blood pressure, drugs that treat arthritis, etc.Specific non-limiting examples are discussed below. In certainembodiments, the drug is one whose are quantified using analyticalmeasurements of the subject (or samples taken from the subject). Often,such drugs have effects cannot be felt by a subject, or cannot bequantified by a subject without analytical measurements beyond a senseof “feeling good.” Examples include, but are not limited to, drugs thatlower cholesterol, drugs that treat anemia, or drugs that treat highblood pressure. In some cases, the drug administered to the subject isnot distinguishable, by the subject and/or by others, from a placebowithout any external equipment (e.g., blood testing). For instance, on atime scale of a day, 2 days, 3 days, a week, 2 weeks, 3 weeks, 4 weeks,etc., the drug is one that would not be distinguishable from a placeboby a typical subject taking the drug. For instance, the effects of thedrug may take a long time to occur, and/or the symptoms treated by thedrug may not be immediately identifiable by the subject (e.g., treatmentof mild anemia) in the absence of any external equipment (e.g., todetermine levels of circulating blood cells).

In certain embodiments, the subject may be one that has or is at riskfor high levels of lipids within the blood, for example, cholesterol. Insome cases, for example, the subject may have total blood cholesterollevel of at least about 200 mg/dl, at least about 210 mg/dl, at leastabout 220 mg/dl, etc.; HDL cholesterol levels of less than about 50mg/dl, less than about 40 mg/dl, less than about 30 mg/dl, etc.,; and/orLDL cholesterol levels of at least about 130 mg/dl, at least about 140mg/dl, at least about 150 mg/dl, etc. Drugs that a subject may take toreduce or lower cholesterol and/or other lipid levels include, but arenot limited to, statins or HMG-CoA reductase inhibitors (e.g.,mevastatin, atorvastatin, cerivastatin, fluvastatin, lovastatin,pitavastatin, pravastatin, rosuvastatin, simvastatin, and/orcombinations of these and/or other compounds), resins (e.g.,cholestyramine, colestipol, or colesevelam), fibrates (e.g.,gemfibrozil, fenofibrate, clofibrate), or niacin, and these may bedetermined in a subject, e.g., in the blood. For instance, a reward maybe presented to a subject after a certain number or frequency ofpositive results where a satisfactory level of a drug was determinedwithin the subject.

In some embodiments, the subject may have or be at risk for anemia, forexample, having a decrease in the number of red blood cells and/orhemoglobin. Drugs useful for treating anemia include, but are notlimited to, iron supplements, folic acid, vitamin B-12, erythropoietinor the like.

The subject may have or be at risk for asthma in some embodiments. Insome cases, the asthma may include occasional asthma attacks. Examplesof drugs usefully for treating asthma include, but are not limited to,long-acting bronchodilators such as beta-2-adrenoceptor agonists,salmeterol, formoterol, bambuterol, or albuterol; steroids such asfluticasone or budesonide; or combinations of these and/or others.

The subject, in some embodiments, may have chronic obstructive pulmonarydisease (COPD) or asthma. Examples of potentially useful drugs to treatconditions such as chronic obstructive pulmonary disease or asthmainclude, but are not limited to, beta-2 agonists such as salbutamol,albuterol, terbutaline, salmeterol, or formoterol; anticholinergics suchas ipratropium or tiotropium; corticosteroids such as prednisone,fluticasone, budesonide, mometasone, or beclomethasone; theophylline; orphosphodiesterase-4 antagonists such as roflumilast or cilomilast.Combinations of these and/or other drugs may also be used in some cases.

In certain embodiments, the subject may have osteoporosis. Theosteoporosis may be treatable by administering drugs such as estrogen,bisphosphonate, calcium, vitamin D, or raloxifene.

In some embodiments, the subject may have diabetes, and may needtreatment, e.g., with insulin. Glucose may be determined in the blood ofthe subject to determine the subject's insulin need and/or compliancewith taking insulin at prescribed times.

In some embodiments, the subject may suffer from various chronic heartdiseases. Characteristics determinable to determine if the subject istaking suitable drugs include, but are not limited to, pulse rate, bloodpressure, or blood measurements such as cholesterol, calcium, sodium,potassium, chloride, bicarbonate, blood urea nitrogen (BUN), magnesium,creatinine, or glucose. Rewards such as external rewards may bepresented if certain goals are met for some or all of these.

In some embodiments, the subject may suffer from inflammatory orimmune-mediated conditions that are subject to periodic “flare-ups” oracute attacks, and the subject accordingly needs to take drugs tocontrol the frequency of such attacks. Examples include, but are notlimited to, arthritis (e.g., rheumatoid arthritis, osteoarthritis,etc.).

In certain embodiments, the subject may be one who is trying to reduceaddiction, e.g., to nicotine or ethanol. Accordingly, nicotine orethanol may be determined in the subject to determine if or to whatdegree the subject has been able to reduce addiction. Additionally,feedback, e.g., in the form of external rewards, etc., may be useful inproviding a positive environment for the subject to continue efforts atreducing the addiction. In some embodiments, the subject may be one whois trying to lose weight. Glucose or other food compounds (e.g.,triglycerides, free amino acids, other sugars, etc.) may be determinedwithin the subject, and optionally, feedback may be provided, to thesubject based on the determination of such compounds.

In some embodiments of the invention, as noted above, a species may bedetermined indirectly, for example, using a tracer of the species. Asused herein, a “tracer” is a substance that can be determined within asubject, typically upon interaction with a tracer indicator. In somecases, the tracer is determinable in some fashion, e.g., by a sensor asdisclosed herein. For example, the tracer may be radioactive orfluorescent in some cases; although in other cases, the tracer may notbe radioactive and/or fluorescent. The determinable change in the tracerand/or the tracer indicator may be a visual change such as a change inappearance (e.g., color), a change in temperature, a change insensation, or the like. The tracer itself may be any suitable compoundthat can be administered to the subject. In some cases, the determinablechange may be determinable using suitable instrumentation.

In some cases, the tracer is chosen to have relatively little biologicalactivity, and can be determined mainly by its interaction with thetracer indicator. However, in other cases, the tracer may have somebiological activity. For instance, the amount of biological activity ofthe tracer within the subject may be predictable. As an example, atracer may be cleared by the kidneys from the bloodstream at a certainrate, and by determining the concentration of tracer within the subject,e.g., by determining a change in a determinable property in a tracerindicator, and correcting for the clearance rate of the tracer, thepharmacokinetic activity of the tracer within the subject may bedetermined, and used to determine the pharmacokinetic activity of asubstance administered to the subject. Usually, the tracer is producedexternally or exogenously, then administered to the subject as discussedbelow. Non-limiting examples of tracers include certain proteins orcarbohydrates such as inulin, or small molecules (typically less thanabout 1000 Da) such as creatinine.

As a non-limiting example, the tracer may exhibit substantially the samepharmacokinetic activity as the substance, or at least exhibit certainpharmacokinetic activities indicative of the substance. For instance,the tracer may exhibit similar absorption and/or distribution rateswithin the body, the same duration within the body, the same metabolismwithin the body, or the same excretion rates from the body, e.g.,through the urine. In other cases, however, the tracer and the substancemay exhibit substantially different pharmacokinetic parameters. Forexample, the tracer may exhibit substantially slower or fasterabsorption or distribution within the body. However, by determining thetracer, e.g., using a tracer indicator, an estimate of thepharmacokinetic activity of the substance within the body may still beobtained. In one embodiment, it may be sufficient to simply determinewhether the tracer is present or absent in the body, and then infer thatthe substance is also present or absent in the body based on the tracer(for example, if the subject is given a composition that comprises boththe tracer and the substance to be administered as a single entity). Insome cases, the amount of tracer delivered to the subject may also becontrolled in some fashion, for example, such that the certainpharmacokinetic activities of the tracer are substantially similar tothe pharmacokinetic activities of the substance also administered to thesubject. As non-limiting examples, the substance may be an alcoholicbeverage or a drug that is administered with a tracer, and the tracerindicator used to determine whether the subject has indeed taken thesubstance or not.

In some aspects, a tracer may be determined in the skin of the subject,or a bodily fluid such as blood or interstitial fluid may be receivedfrom a subject and the tracer determined within the received fluid,thereby indicating the presence and/or amount of tracer within thesubject. Thus, in some embodiments, a tracer may be determined inassociation with the subject, i.e., the tracer may be determined whilethe tracer is physically within the subject, e.g., within the skin ofthe subject, and/or the tracer may be determined after being removedfrom the subject in some fashion, e.g., by being recevied within abodily fluid such as blood or interstitial fluid. The tracer istypically, but need not be, an auxiliary species administered along withthe substance, the presence and/or quantity of which is to be determinedin association with the subject, and in many cases the tracer has nopurpose in relation to the subject other than its function as a tracer.

An “tracer indicator” is a species that exhibits a change in adeterminable property upon interaction with a tracer. However, it shouldbe understood that a tracer indicator is not necessarily required in allembodiments of the invention. In some cases, the tracer itself isdeterminable in some fashion. For example, the tracer may be radioactiveor fluorescent in some cases, although in other cases, the tracer maynot be radioactive and/or fluorescent. The determinable change in thetracer and/or the tracer indicator may be a visual change such as achange in appearance (e.g., color), a change in temperature, a change insensation, or the like. The tracer itself may be any suitable compoundthat can be administered to the subject. In some cases, the determinablechange may be one that can be determined by a human without the use ofany equipment, for example, visually, tactilely, or the like. In othercases, however, the determinable change may be determinable usingsuitable instrumentation.

In some cases, the tracer is chosen to have relatively little, oressentially no, biological activity, and can be determined mainly by itsinteraction with the tracer indicator. However, in other cases, thetracer may have some biological activity. For instance, the amount ofbiological activity of the tracer within the subject may be predictable.As an example, a tracer may be cleared by the kidneys from thebloodstream at a certain rate, and by determining the concentration oftracer within the subject, e.g., by determining a change in adeterminable property in a tracer indicator, and correcting for theclearance rate of the tracer, the pharmacokinetic activity of the tracerwithin the subject may be determined, and used to determine thepharmacokinetic activity of a substance administered to the subject.Usually, the tracer is produced externally or exogenously, thenadministered to the subject as discussed below. Non-limiting examples oftracers include certain proteins or carbohydrates such as inulin, orsmall molecules (typically less than about 1000 Da) such as creatinine.

The tracer may be relatively non-toxic in some cases. In certainembodiments, the tracer is a molecule that has a relatively high rate ofclearance from the body. For instance, the half-life of the tracerwithin the body may be less than about 3 days, less than about 2 days,less than about 1 day, less than about 18 hours, less than about 12hours, less than about 9 hours, less than about 3 hours, or less thanabout 1 hour. In some cases, the tracer may include poly(ethylene)glycol, for example, PEG 300, PEG 400, PEG 2000, PEG 3350, or PEG 8000(where “PEG” stands for poly(ethylene) glycol and the number indicatesthe molecular weight).

As a non-limiting example, the tracer may exhibit substantially the samepharmacokinetic activity as the substance, or at least exhibit certainpharmacokinetic activities indicative of the substance. For instance,the tracer may exhibit similar absorption and/or distribution rateswithin the body, the same duration within the body, the same metabolismwithin the body, or the same excretion rates from the body, e.g.,through the urine. In other cases, however, the tracer and the substancemay exhibit substantially different pharmacokinetic parameters. Forexample, the tracer may exhibit substantially slower or fasterabsorption or distribution within the body. However, by determining thetracer, e.g., using a tracer indicator, an estimate of thepharmacokinetic activity of the substance within the body may still beobtained. In one embodiment, it may be sufficient to simply determinewhether the tracer is present or absent in the body, and then infer thatthe substance is also present or absent in the body based on the tracer(for example, if the subject is given a composition that comprises boththe tracer and the substance to be administered as a single entity). Insome cases, the amount of tracer delivered to the subject may also becontrolled in some fashion, for example, such that the certainpharmacokinetic activities of the tracer are substantially similar tothe pharmacokinetic activities of the substance also administered to thesubject. The substance may be any substance to be delivered to asubject, in which a determination of the substance within the subject isdesired. As non-limiting examples, the substance may be an alcoholicbeverage or a drug that is administered with a tracer, and the tracerindicator used to determine whether the subject has indeed taken thesubstance or not. For example, the subject may be one who has troublewith memory; by visually determining a tracer indicator (e.g., in theskin), whether the tracer (and thus, the substance) has beenadministered (or self-administered) to the subject may be determined.

The tracer may be administered to the subject using any suitable method.For example, the tracer may be administered orally, vaginally, rectally,buccally, pulmonary, topically, nasally, transdermally, throughparenteral injection or implantation, via surgical administration, orany other suitable method of administration. The tracer may be deliveredsystemically, or in some cases locally, e.g., at a site proximate atracer indicator. The tracer may also be administered by the subject(i.e., self-administered), or offered and/or administered to the subjectby someone else, e.g., a doctor or a nurse. In addition, techniquesdiscussed below that may be useful for delivering a tracer indicator toa subject may also be useful for delivering a tracer to the subject. Asdiscussed, the tracer and the tracer indicator need not be deliveredusing the same route of administration (although they can be), and theyalso need not be delivered simultaneously. For example, the tracerindicator may be rubbed onto the surface of the skin or injected intothe skin, while the tracer may be delivered orally, or injected into thebloodstream of the subject.

The tracer may interact with a tracer indicator within the subject. Asmentioned, a tracer indicator is a species that can interact with thetracer and exhibit a change in a determinable property upon such aninteraction. For instance, the tracer indicator may change appearance orcolors in the presence or in the absence of the tracer, e.g., the tracerindicator may exhibit a first color at a first concentration of thetracer and a second color at a second concentration of the tracer, orthe tracer may exhibit a range of colors depending on the concentrationof the tracer. The tracer indicator may, in certain cases, beimmobilized within the subject, e.g., within a depot in the skin. Forinstance, the tracer indicator may be immobilized such that at leastabout 90% or at least about 95% of the tracer indicator administered tothe subject stays in the location in which it was administered. In somecases, the change can be determined by a human without the use of anyequipment. Non-limiting examples include changes in appearance (e.g.,color), temperature changes, chemical reactions (e.g., capsaicin) whichcan be sensed by the subject (e.g., as a feeling of pain), or the like.Examples of capsaicin and capsaicin-like molecules include, but are notlimited to, dihydrocapsaicin, nordihydrocapsaicin, homodihydrocapsaicin,homocapsaicin, or nonivamide.

As additional examples, the tracer indicator may include antibodies,enzymes, indicator dyes, or the like which are able to interact with atracer, and which may exhibit a change in a determinable property, suchas a change in color or aggregation, upon such an interaction. As anon-limiting example, in one embodiment, a tracer indicator comprisingan antibody may bind to a tracer (e.g., inulin), and upon binding,aggregation of antibodies (e.g., multiple antibodies to the same target,primary antibodies and secondary antibodies where the secondary antibodyis labeled, etc.) may be used to determine the tracer. Those of ordinaryskill in the art will know of techniques for raising tracer indicatorssuch as antibodies against a specific target.

In one aspect, the invention is generally directed to methods foradministering a tracer or other compound to a subject, remotely and/orwithout their knowledge, even in cases where the subject is conscious ornot asleep. For example, a tracer may be injected into a subject using adevice as discussed herein, or other device. In some cases, for example,the device may be relatively small and unobtrusive, and/or produceminimal pain or sensation such that the subject is not conscious of thedevice's actions. For example, a fluid or a tracer may be injected tothe subject using one or more microneedles as discussed herein. Examplesof devices having such microneedles are disclosed herein; additionalexamples may be seen in a U.S. application being filed on even dateherewith, entitled “Clinical and/or Consumer Techniques and Devices”;and in U.S. Apl. Ser No. 61/373,764, entitled “Clinical and/or ConsumerTechniques and Devices,” each of which is incorporated herein byreference in its entirety.

The tracer may then be subsequently determined to determine the subject.For example, in certain embodiments, the tracer is covertly applied to asubject, without the subject's knowledge, and the tracer used todetermine movements of the subject. As a specific non-limiting example,it can be determined whether or not the subject passed a certainlocation (and thus was subjected to the tracer). For example, thesubject may pass a first location, where the tracer is covertly appliedto the subject, then the subject may be tested at a second location,wherein the presence of the tracer is covertly determined, e.g., bycovertly receiving blood from the subject using a device such as isdescribed herein. If the subject passed the first location, the tracerwill be detected in the blood of the subject at the second location;however, if the subject never passed the first location (e.g., thesubject used a different route), then no tracer will be detected in theblood of the subject at the second location. Thus, movement of thesubject may be tracked by monitoring the tracer within the subject.

In some embodiments, the tracer is used to determine a condition, suchas a medical condition, of the subject, for example dehydration. Thetracer may be, for example, an inert compound (e.g., inulin), afluorescent compound, or the like, and may be determined by any suitabletechnique, e.g., fluorescence, urine samples, or the like. Additionalexamples of tracers also include proteins or carbohydrates such asinulin, or small molecules (typically less than about 1000 Da) such ascreatinine. In some cases, the tracer may include poly(ethylene) glycol,for example, PEG 300, PEG 400, PEG 2000, PEG 3350, or PEG 8000 (where“PEG” stands for poly(ethylene) glycol and the number indicates themolecular weight). Further examples of tracers are disclosed inInternational Patent Application No. PCT/US2010/000919, entitled“Determination of Tracers Within Subjects,” filed on Mar. 26, 2010,incorporated herein by reference in its entirety.

In some cases, the device is a covert device, i.e., the device is formedinto a something that does not appear to be a medical device. Forexample, the device may be embedded within a chair, a book, an umbrella,or a steering wheel, such that the device is able to inject a fluid ortracer into a subject without the subject ever being aware that thesubject was exposed to the device. For example, by injecting a subjectwith a tracer, movements of the subject may be determined, for example,if the subject goes through an area they are not authorized to enter, orpasses through an area of concern, such as a terrorist training camp ora military base.

In some embodiments, the device may be used to monitor a population ofindividuals. For example, the population may be a population entering acertain area (e.g., a border region, a town, a neighborhood, etc.), apopulation of subjects in a hospital, a medical facility, a nursinghome, a school, or the like. Subjects having the tracer (knowingly ornot) may be identified and distinguished from subjects not having thetracer, for example, as is discussed herein. Such data may be used, forexample, for epidemiological purposes, to track the spread of diseases(such as contagious diseases, e.g., influenza or colds), to monitor thehealth of the population, to audit the performance of an institution(e.g., a hospital, a nursing home, a school), or the like. In somecases, such data may be used to set up quarantines, e.g., in the case ofinfectious diseases. In certain instances, such data may also becombined with additional data, for example, positional data from GPSsystems or the like, as is discussed herein.

In certain embodiments, a fluid such as blood may be received from apopulation of individuals. For instance, devices including microneedles,or other devices such as those described herein, may be used to receiveblood from patients (knowingly or otherwise), and then a condition ofthe subject determined, e.g., by determining an analyte within the blood(or other fluid). Examples of analytes determinable in a subjectinclude, but are not limited to, glucose, tracers such as inulin, ions,or the like. Accordingly, characteristics of the population ofindividuals may be determined by determining the analyte in certainembodiments.

In some aspects, the device may be sold together with the drug or otherpharmaceutical, e.g., as part of a kit. For example, the kit may includea drug or other pharmaceutical, and a device able to determine a specieswithin the skin of a subject, e.g., a species indicative of the drug orother pharmaceutical, as previously discussed. In other embodiments,however, the device may be sold separately from the drug or otherpharmaceutical. For example, a doctor or other medical personnel mayprescribe a drug (or other pharmaceutical) to a subject, and optionally,the doctor or other medical personnel may prescribe a device of theinvention, either separately, or together (e.g., as in a kit). In somecases, however, the device itself may be readily available to thesubject, e.g., obtainable over-the-counter (OTC) or without aprescription. It should be noted that even if the drug itself requires aprescription, if the device is sold separately (without the drug), itneed not necessarily also require a prescription to be purchased.Further examples of kits are discussed in detail below.

As previously discussed, in some embodiments, the device is able todeliver and/or receive fluid from the skin of a subject, or othermucosal surface, as well as methods of use thereof. In some cases, thedevice may pierce the skin of the subject, and fluid can then bedelivered and/or received from the subject. The subject is usuallyhuman, although non-human subjects may be used in certain instances, forinstance, other mammals such as a dog, a cat, a horse, a rabbit, a cow,a pig, a sheep, a goat, a rat (e.g., Rattus Norvegicus), a mouse (e.g.,Mus musculus), a guinea pig, a hamster, a primate (e.g., a monkey, achimpanzee, a baboon, an ape, a gorilla, etc.), or the like. If a fluidis received from the subject, the fluid may be any suitable bodilyfluid. In certain embodiments, essentially any body fluid can be used,such as interstitial fluid, other skin-associated material, mucosalmaterial or fluid, whole blood, perspiration and saliva, plasma, or anyother bodily fluid.

Non-limiting examples of various devices of the invention are shown inFIG. 1. In FIG. 1A, device 90 is used for receiving a fluid from asubject when the device is placed on the skin of a subject. Device 90includes sensor 95 and substance transfer component 92, e.g., includinga needle, a microneedle, etc., as discussed herein. In fluidiccommunication with substance transfer component 92 via fluidic channel99 is sensing chamber 97. In one embodiment, sensing chamber 97 maycontain agents such as particles, enzymes, dyes, etc., for analyzingbodily fluids, such as interstitial fluid or blood. In some cases, fluidmay be received using substance transfer component 92 by a vacuum, forexample, a self-contained vacuum contained within device 90. Optionally,device 90 also contains a display 94 and associated electronics 93,batteries or other power supplies, etc., which may be used to displaysensor readings obtained via sensor 95. In addition, device 90 may alsooptionally contain memory 98, transmitters for transmitting a signalindicative of sensor 95 to a receiver, etc.

In the example shown in FIG. 1A, device 90 may contain a vacuum source(not shown) that is self-contained within device 90, although in otherembodiments, the vacuum source may be external to device 90. (In stillother instances, other systems may be used to deliver and/or receivefluid from the skin, as is discussed herein.) In one embodiment, afterbeing placed on the skin of a subject, the skin may be drawn upward intoa recess of the substance transfer component 92, for example, uponexposure to the vacuum source. Access to the vacuum source may becontrolled by any suitable method, e.g., by piercing a seal or a septum;by opening a valve or moving a gate, etc. For instance, upon activationof device 90, e.g., by the subject, remotely, automatically, etc., thevacuum source may be put into fluidic communication with the recess suchthat skin is drawn into the recess due to the vacuum. Skin drawn intothe recess may come into contact with a skin insertion object (e.g.,solid or hollow needles), which may, in some cases, pierce the skin andallow a fluid to be delivered and/or received from the skin. In anotherembodiment, a skin insertion object may be actuated and moved downwardto come into contact with the skin, and optionally retracted after use.

Another non-limiting example of a device is shown in FIG. 1B. Thisfigure illustrates a device useful for delivering a fluid to thesubject. Device 90 in this figure includes substance transfer component92, e.g., including a needle, a microneedle, etc., as discussed herein.In fluidic communication with substance transfer component 92 viafluidic channel 99 is chamber 97, which may contain a drug or otheragent to be delivered to the subject. In some cases, fluid may bedelivered with a pressure controller, and/or received using substancetransfer component 92 by a vacuum, for example, a self-contained vacuumcontained within device 90. For instance, upon creating a vacuum, skinmay be drawn up towards substance transfer component 92, and thesubstance transfer component 92 may pierce the skin. Fluid from chamber97 can then be delivered into the skin through fluid channel 99 andsubstance transfer component 92. Optionally, device 90 also contains adisplay 94 and associated electronics 93, batteries or other powersupplies, etc., which may be used control delivery of fluid to the skin.In addition, device 90 may also optionally contain memory 98,transmitters for transmitting a signal indicative of device 90 or fluiddelivery to a receiver, etc.

Yet another non-limiting example of a device of the invention is shownin FIG. 2. FIG. 2A illustrates a view of the device (with the coverremoved), while FIG. 2B schematically illustrates the device incross-section. In FIG. 2B, device 50 includes a needle 52 containedwithin a recess 55. Needle 52 may be solid or hollow, depending on theembodiment. Device 50 also includes a self-contained vacuum chamber 60,which wraps around the central portion of the device where needle 52 andrecess 55 are located. A channel 62 connects vacuum chamber 60 withrecess 55, separated by a foil or a membrane 67. Also shown in device 50is button 58. When pushed, button 58 breaks foil 67, thereby connectingvacuum chamber 50 with recess 55, creating a vacuum in recess 55. Thevacuum may be used, for example, to draw skin into recess 55, preferablysuch that it contacts needle 52 and pierces the surface, thereby gainingaccess to an internal fluid. The fluid may be controlled, for example,by controlling the size of needle 52, and thereby the depth ofpenetration. For example, the penetration may be limited to theepidermis, e.g., to collect interstitial fluid, or to the dermis, e.g.,to collect blood. In some cases, the vacuum may also be used to at leastpartially secure device 50 on the surface of the skin, and/or to assistin the receiving of fluid from the skin. For instance, fluid may flowinto channel 62 under action of the vacuum, and optionally to sensor 61,e.g., for detection of an analyte contained within the fluid. Forinstance, sensor 61 may produce a color change if an analyte is present,or otherwise produce a detectable signal.

Other components may be added to the example of the device illustratedin FIG. 2, in some embodiments of the invention. For example, device 50may contain a cover, displays, ports, transmitters, sensors, channelssuch as microfluidic channels, chambers, and/or various electronics,e.g., to control or monitor fluid transport into or out of device 50, todetermine an analyte present within a fluid delivered and/or receivedfrom the skin, to determine the status of the device, to report ortransmit information regarding the device and/or analytes, or the like,as is discussed in more detail herein. As another example, device 50 maycontain an adhesive, e.g., on surface 54, for adhesion of the device tothe skin.

Yet another non-limiting example is illustrated with reference to FIG.2C. In this example, device 500 includes a housing 501, and anassociated substance transfer component 503. Substance transfercomponent 503 includes a plurality of needles or microneedles 505,although other skin insertion objects or flow activators as discussedherein may also be used.

Also shown in FIG. 2C is sensor 510, connected via channels 511 torecess 508 containing needles or microneedles 505. Chamber 513 may be aself-contained vacuum chamber, and chamber 513 may be in fluidiccommunication with recess 508 via channel 511, for example, ascontrolled by a controller or an actuator (not shown). In this figure,device 500 also contains display 525, which is connected to sensor 510via electrical connection 522. As an example of use of device 500, whenfluid is drawn from the skin (e.g., blood, interstitial fluid, etc.),the fluid may flow through channel 511 to be determined by sensor 510,e.g., due to action of the vacuum from vacuum chamber 513. In somecases, the vacuum is used, for example, to draw skin into recess 508,preferably such that it contacts needles or microneedles 505 and piercesthe surface of the skin to gain access to a fluid internal of thesubject, such as blood or interstitial fluid, etc. The fluid may becontrolled, for example, by controlling the size of needle 505, andthereby the depth of penetration. For example, the penetration may belimited to the epidermis, e.g., to collect interstitial fluid, or to thedermis, e.g., to collect blood. Upon determination of the fluid and/oran analyte present or suspected to be present within the fluid, amicroprocessor or other controller may display on display 525 a suitablesignal. As is discussed below, a display is shown in this figure by wayof example only; in other embodiments, no display may be present, orother signals may be used, for example, lights, smell, sound, feel,taste, or the like.

In some cases, more than one substance transfer component may be presentwithin the device. For instance, the device may be able to be usedrepeatedly, and/or the device may be able to deliver and/or receivefluid at more than one location on a subject, e.g., sequentially and/orsimultaneously. In some cases, the device may be able to simultaneouslydeliver and receive fluid to and from a subject. A non-limiting exampleof a device having more than one substance transfer component isillustrated with reference to FIG. 2E. In this example, device 500contains a plurality of structures such as those described herein fordelivering and/or receiving fluid from a subject. For example, device500 in this example contains 3 such units, although any number of unitsare possible in other embodiments. In this example, device 500 containsthree such substance transfer components 575. Each of these substancetransfer components may independently have the same or differentstructures, depending on the particular application, and they may havestructures such as those described herein.

In some embodiments, the device may be an electrical and/or a mechanicaldevice applicable or affixable to the surface of the skin, e.g., usingadhesive, or other techniques such as those described herein. Theadhesive may be permanent or temporary, and may be used to affix thedevice to the surface of the skin. The adhesive may be any suitableadhesive, for example, a pressure sensitive adhesive, a contactadhesive, a permanent adhesive, a hydrogel, a cyanoacrylate, a glue, agum, hot melts, an epoxy, or the like. In some cases, the adhesive ischosen to be biocompatible or hypoallergenic.

As another example, the device may be a handheld device that is appliedto the surface of the skin of a subject. In some cases, however, thedevice may be sufficiently small or portable that the subject canself-administer the device. In certain embodiments, the device may alsobe powered. In some instances, the device may be applied to the surfaceof the skin, and is not inserted into the skin. In other embodiments,however, at least a portion of the device may be inserted into the skin,for example, mechanically. For example, in one embodiment, the devicemay include a cutter, such as a hypodermic needle, a knife blade, apiercing element (e.g., a solid or hollow needle), or the like, asdiscussed herein.

In some cases, the device may be designed such that portions of thedevice are separable. For example, a first portion of the device may beremoved from the surface of the skin, leaving other portions of thedevice behind on the skin. In one embodiment, a stop may also beincluded to prevent or control the depth to which the cutter or otherdevice inserts into the skin, e.g., to control penetration to theepidermis, dermis, etc.

Any or all of the arrangements described herein can be providedproximate a subject, for example on or proximate a subject's skin.Activation of the devices can be carried out as described herein. Forexample, an on-skin device can be in the form of a patch or the like,optionally including multiple layers for activation, sensing, fluidflow, etc. Activation of the devices can be carried out in a variety ofways. In one manner, a patch can be applied to a subject and a region ofthe patch activated (e.g., tapped by a user) to inject a microneedle soas to access interstitial fluid. The same or a different tapping orpushing action can activate a vacuum source, open and/or close one ormore of a variety of valves, or the like. The device can be a simple onein which it is applied to the skin and operates automatically (wheree.g., application to the skin access interstitial fluid and drawsinterstitial fluid into an analysis region) or the patch or other devicecan be applied to the skin and one tapping or other activation can causefluid to flow through administration of a microneedle, opening of avalve, activation of vacuum, or any combination. Any number ofactivation protocols can be carried out by a user repeatedly pushing ortapping a location or selectively, sequentially, and/or periodicallyactivating a variety of switches (e.g., tapping regions of a patch).With this description, those of ordinary skill in the art can understandhow any of the assays described above with respect to one and two can befacilitated. In another arrangement, activation of microneedles,creation of suction blisters, opening and/or closing of valves, andother techniques to facilitate one or more analysis can be carried outelectronically or in other manners facilitated by the subject or by anoutside controlling entity. For example, a device or patch can beprovided proximate a subject's skin and a radio frequency,electromagnetic, or other signal can be provided by a nearby controlleror a distant source to activate any of the needles, blister devices,valves or other components of the devices described so that any assay orassays can be carried out as desired.

As discussed, various devices of the invention include various systemsand methods for delivering and/or receiving fluid from the subject,according to certain embodiments. For instance, the device may comprisea hypodermic needle, a vacuum source, a hygroscopic agent, or the like.Non-limiting examples of suitable delivery techniques include, but arenot limited to, injection (e.g., using needles such as hypodermicneedles) or a jet injector, such as those discussed below. For instance,in one embodiment, the fluid is delivered and/or received manually,e.g., by manipulating a plunger on a syringe. In another embodiment, thefluid can be delivered and/or received from the skin mechanically orautomatically, e.g., using a piston pump or the like. Fluid may also bereceived using vacuums such as those discussed herein. For example,vacuum may be applied to a conduit, such as a needle, in fluidiccommunication with interstitial fluid. In yet another embodiment, fluidis received using capillary action (e.g., using a hypodermic needlehaving a suitably narrow inner diameter). In still another embodiment,pressure may be applied to force fluid out of the needle.

For instance, fluids received from the subject will often containvarious analytes within the body that are important for diagnosticpurposes, for example, markers for various disease states, such asglucose (e.g., for diabetics); other example analytes include ions suchas sodium, potassium, chloride, calcium, magnesium, and/or bicarbonate(e.g., to determine dehydration); gases such as carbon dioxide oroxygen; H⁺ (i.e., pH); metabolites such as urea, blood urea nitrogen orcreatinine; hormones such as estradiol, estrone, progesterone,progestin, testosterone, androstenedione, etc. (e.g., to determinepregnancy, illicit drug use, or the like); or cholesterol. Otherexamples include insulin, or hormone levels. As discussed herein,certain embodiments of the present invention are generally directed atmethods for receiving fluids from the body, and optionally determiningone or more analytes within the received fluid. Thus, in someembodiments, at least a portion of the fluid may be stored, and/oranalyzed to determine one or more analytes, e.g., a marker for a diseasestate, or the like. The fluid received from the skin may be subjected tosuch uses, and/or one or more materials previously delivered to the skinmay be subject to such uses.

In other embodiments, fluid may be delivered to the subject, and suchfluids may contain materials useful for delivery, e.g., forming at leasta portion of the fluid, dissolved within the fluid, carried by the fluid(e.g., suspended or dispersed), or the like. Examples of suitablematerials include, but are not limited to, particles such asmicroparticles or nanoparticles, a chemical, a drug or a therapeuticagent, a diagnostic agent, a carrier, or the like.

As used herein, the term “fluid” generally refers to a substance thattends to flow and to conform to the outline of its container. Typically,fluids are materials that are unable to withstand a static shear stress,and when a shear stress is applied, the fluid experiences a continuingand permanent distortion. The fluid may have any suitable viscosity thatpermits at least some flow of the fluid. Non-limiting examples of fluidsinclude liquids and gases, but may also include free-flowing solidparticles, viscoelastic fluids, and the like. For example, the fluid mayinclude a flowable matrix or a gel, e.g., formed from biodegradableand/or biocompatible material such as polylactic acid, polyglycolicacid, poly(lactic-co-glycolic acid), etc., or other similar materials.

In other cases, however, the materials delivered to the subject may beused to determine conditions that are external to the subject. Forexample, the materials may contain reaction entities able to recognizepathogens or other environmental conditions surrounding the subject, forexample, an antibody able to recognize an external pathogen (or pathogenmarker). As a specific example, the pathogen may be anthrax and theantibody may be an antibody to anthrax spores. As another example, thepathogen may be a Plasmodia (some species of which causes malaria) andthe antibody may be an antibody that recognizes the Plasmodia.

According to one set of embodiments, many devices as discussed hereinuse various techniques for delivering and/or receiving fluid, forexample, in connection with substance transfer components, skininsertion objects, or the like. For example, one or more needles and/ormicroneedles, a hygroscopic agent, a cutter or other piercing element,an electrically-assisted system, or the like may be used in conjunctionwith a snap dome or other device as described above. Additional examplesof such techniques are described herein and/or in the applicationsincorporated herein. It is to be understood that, generally, fluids maybe delivered and/or received in a variety of ways, and various systemsand methods for delivering and/or receiving fluid from the skin (orother organs) are discussed below and/or in the applicationsincorporated herein. In some embodiments, for example, techniques forpiercing or altering the surface of the skin to transport a fluid arediscussed, for example, using a needle such as a hypodermic needle ormicroneedles, chemicals applied to the skin (e.g., penetrationenhancers), jet injectors or other techniques such as those discussedbelow, etc.

As an example, in one embodiment, a needle such as a hypodermic needlecan be used to deliver and/or receive fluid to or from the skin or otherorgan. Hypodermic needles are well-known to those of ordinary skill inthe art, and can be obtained commercially with a range of needle gauges.For example, the needle may be in the 20-30 gauge range, or the needlemay be 32 gauge, 33 gauge, 34 gauge, etc.

As an example, microneedles such as those disclosed in U.S. Pat. No.6,334,856, issued Jan. 1, 2002, entitled “Microneedle Devices andMethods of Manufacture and Use Thereof,” by Allen, et al., may be usedto deliver and/or receive fluids or other materials to or from asubject. The microneedles may be hollow or solid, and may be formed fromany suitable material, e.g., metals, ceramics, semiconductors, organics,polymers, and/or composites. Examples include, but are not limited to,pharmaceutical grade stainless steel, gold, titanium, nickel, iron,gold, tin, chromium, copper, alloys of these or other metals, silicon,silicon dioxide, and polymers, including polymers of hydroxy acids suchas lactic acid and glycolic acid polylactide, polyglycolide,polylactide-co-glycolide, and copolymers with polyethylene glycol,polyanhydrides, polyorthoesters, polyurethanes, polybutyric acid,polyvaleric acid, polylactide-co-caprolactone, polycarbonate,polymethacrylic acid, polyethylenevinyl acetate, polytetrafluorethylene,or polyesters.

In some cases, more than one microneedle may be used. For example,arrays of microneedles may be used, and the microneedles may be arrangedin the array in any suitable configuration, e.g., periodic, random, etc.In some cases, the array may have 3 or more, 4 or more, 5 or more, 6 ormore, 10 or more, 15 or more, 20 or more, 35 or more, 50 or more, 100 ormore, or any other suitable number of microneedles. In some embodiments,the device may have at least 3 but no more than 5 needles ormicroneedles (or other skin insertion objects), at least 6 but no morethan 10 needles or microneedles, or at least 11 but no more than 20needles or microneedles. Typically, a microneedle will have an averagecross-sectional dimension (e.g., diameter) of less than about a micron.It should be understood that references to “needle” or “microneedle” asdiscussed herein are by way of example and ease of presentation only,and that in other embodiments, more than one needle and/or microneedlemay be present in any of the descriptions herein.

As still another example, pressurized fluids may be used to deliverfluids or other materials into the skin, for instance, using a jetinjector or a “hypospray.” Typically, such devices produce ahigh-pressure “jet” of liquid or powder (e.g., a biocompatible liquid,such as saline) that drives material into the skin, and the depth ofpenetration may be controlled, for instance, by controlling the pressureof the jet. The pressure may come from any suitable source, e.g., astandard gas cylinder or a gas cartridge. A non-limiting example of sucha device can be seen in U.S. Pat. No. 4,103,684, issued Aug. 1, 1978,entitled “Hydraulically Powered Hypodermic Injector with Adapters forReducing and Increasing Fluid Injection Force,” by Ismach.Pressurization of the liquid may be achieved, for example, usingcompressed air or gas, for instance, from a gas cylinder or a gascartridge.

In some embodiments, fluid may be received using a hygroscopic agentapplied to the surface of the skin, or proximate the skin. For example,a device as described herein may contain a hygroscopic agent. In somecases, pressure may be applied to drive the hygroscopic agent into theskin. Hygroscopic agents typically are able to attract water from thesurrounding environment, for instance, through absorption or adsorption.Non-limiting examples of hygroscopic agents include sugar, honey,glycerol, ethanol, methanol, sulfuric acid, methamphetamine, iodine,many chloride and hydroxide salts, and a variety of other substances.Other examples include, but are not limited to, zinc chloride, calciumchloride, potassium hydroxide, or sodium hydroxide. In some cases, asuitable hygroscopic agent may be chosen based on its physical orreactive properties, e.g., inertness or biocompatibility towards theskin of the subject, depending on the application.

In some embodiments, the device may comprise a cutter able to cut orpierce the surface of the skin. The cutter may comprise any mechanismable to create a path through which fluids may be delivered and/orreceived from the skin. For example, the cutter may comprise ahypodermic needle, a blade (e.g., a knife blade, a serrated blade,etc.), a piercing element (e.g., a lancet or a solid or a hollowneedle), or the like, which can be applied to the skin to create asuitable conduit for the delivery and/or receiving of fluid from theskin. In one embodiment, a cutter is used to create such a pathway andremoved, then fluid may be delivered and/or received via this pathway.In another embodiment, the cutter remains in place within the skin, andfluid may be delivered and/or received through a conduit within thecutter.

In some embodiments, fluid may be received using an electric charge. Forexample, reverse iontophoresis may be used. Without wishing to be boundby any theory, reverse iontophoresis uses a small electric current todrive charged and highly polar compounds across the skin. Since the skinis negatively charged at physiologic pH, it acts as a permselectivemembrane to cations, and the passage of counterions across the skininduces an electroosmotic solvent flow that may carry neutral moleculesin the anode-to-cathode direction. Components in the solvent flow may beanalyzed as described elsewhere herein. In some instances, a reverseiontophoresis apparatus may comprise an anode cell and a cathode cell,each in contact with the skin. The anode cell may be filled, forexample, with an aqueous buffer solution (i.e., aqueous Tris buffer)having a pH greater than 4 and an electrolyte (i.e. sodium chloride).The cathode cell can be filled with aqueous buffer. As one example, afirst electrode (e.g., an anode) can be inserted into the anode cell anda second electrode (e.g., a cathode) can be inserted in the cathodecell. In some embodiments, the electrodes are not in direct contact withthe skin.

A current may be applied to induce reverse iontophoresis, therebyreceiving a fluid from the skin. The current applied may be, forexample, greater than 0.01 mA, greater than 0.3 mA, greater than 0.1 mA,greater than 0.3 mA, greater than 0.5 mA, or greater than 1 mA. Itshould be understood that currents outside these ranges may be used aswell. The current may be applied for a set period of time. For example,the current may be applied for greater than 30 seconds, greater than 1minute, greater than 5 minutes, greater than 30 minutes, greater than 1hour, greater than 2 hours, or greater than 5 hours. It should beunderstood that times outside these ranges may be used as well.

In one set of embodiments, the device may comprise a substance transfercomponent in the form of an apparatus for ablating the skin. Withoutwishing to be bound by any theory, it is believed that ablationcomprises removing a microscopic patch of stratum corneum (i.e.,ablation forms a micropore), thus allowing access to bodily fluids. Insome cases, thermal, radiofrequency, and/or laser energy may be used forablation. In some instances, thermal ablation may be applied using aheating element. Radiofrequency ablation may be carried out using afrequency and energy capable of heating water and/or tissue. A laser mayalso be used to irradiate a location on the skin to remove a portion. Insome embodiments, the heat may be applied in pulses such that a steeptemperature gradient exists essentially perpendicular to the surface ofthe skin. For example, a temperature of at least 100° C., at least 200°C., at least 300° C., or at least 400° C. may be applied for less than 1second, less than 0.1 seconds, less than 0.01 seconds, less than 0.005seconds, or less than 0.001 seconds.

In some embodiments, the device may comprise a substance transfercomponent in the form of a mechanism for taking a solid sample oftissue. For example, a solid tissue sample may be acquired by methodssuch as scraping the skin or cutting out a portion. Scraping maycomprise a reciprocating action whereby an instrument is scraped alongthe surface of the skin in two or more directions. Scraping can also beaccomplished by a rotating action, for example parallel to the surfaceof the skin and in one direction (i.e., with a roller drum) or parallelto the surface of the skin and in a circular manner (i.e., with adrilling instrument). A cutting mechanism may comprise a blade capableof making one or more incisions and a mechanism for removing a portionof tissue (i.e., by suction or mechanically picking up) or may use apincer mechanism for cutting out a portion of tissue. A cuttingmechanism may also function by a coring action. For example, a hollowcylindrical device can be penetrated into the skin such that acylindrical core of tissue may be removed. A solid sample may beanalyzed directly or may be liquefied prior to analysis. Liquefactioncan comprise treatment with organic solvents, enzymatic solutions,surfactants, etc.

In some embodiments, fluids may be delivered to or received from theskin using vacuum. The vacuum may be an external vacuum source, and/orthe vacuum source may be self-contained within the device. For example,vacuums of at least about 50 mmHg, at least about 100 mmHg, at leastabout 150 mmHg, at least about 200 mmHg, at least about 250 mmHg, atleast about 300 mmHg, at least about 350 mmHg, at least about 400 mmHg,at least about 450 mmHg, at least about 500 mmHg, at least 550 mmHg, atleast 600 mmHg, at least 650 mmHg, at least about 700 mmHg, or at leastabout 750 mmHg may be applied to the skin. As used herein, “vacuum”refers to pressures that are below atmospheric pressure.

As mentioned, any source of vacuum may be used. For example, the devicemay comprise an internal vacuum source, and/or be connectable to avacuum source is external to the device, such as a vacuum pump or anexternal (line) vacuum source. In some cases, vacuum may be createdmanually, e.g., by manipulating a syringe pump, a plunger, or the like,or the low pressure may be created mechanically or automatically, e.g.,using a piston pump, a syringe, a bulb, a Venturi tube, manual (mouth)suction, etc., or the like.

In one set of embodiments, a device of the present invention may nothave an external power and/or a vacuum source. In some cases, the deviceis “pre-loaded” with a suitable vacuum source; for instance, in oneembodiment, the device may be applied to the skin and activated in somefashion to create and/or access the vacuum source. As one example, adevice of the present invention may be contacted with the skin of asubject, and a vacuum created through a change in shape of a portion ofthe device (e.g., using a shape memory polymer), or the device maycontain one or more sealed, self-contained vacuum chambers, where a sealis punctured in some manner to create a vacuum. For instance, uponpuncturing the seal, a vacuum chamber may be in fluidic communicationwith a needle, which can be used to move the skin towards the device,receive fluid from the skin, or the like.

In some embodiments, the device may be an electrical and/or a mechanicaldevice applicable or affixable to the surface of the skin, e.g., usingadhesive, or other techniques such as those described herein. Theadhesive may be permanent or temporary, and may be used to affix thedevice to the surface of the skin. The adhesive may be any suitableadhesive, for example, a pressure sensitive adhesive, a contactadhesive, a permanent adhesive, a hydrogel, a cyanoacrylate, a glue, agum, hot melts, an epoxy, or the like. In some cases, the adhesive ischosen to be biocompatible or hypoallergenic.

In another set of embodiments, the device may be mechanically held tothe skin, for example, the device may include mechanical elements suchas straps, belts, buckles, strings, ties, elastic bands, or the like.For example, a strap may be worn around the device to hold the device inplace against the skin of the subject. In yet another set ofembodiments, a combination of these and/or other techniques may be used.As one non-limiting example, the device may be affixed to a subject'sarm or leg using adhesive and a strap.

In some embodiments, the device may include a support structure forapplication to the skin of the subject. The support structure may beused, as discussed herein, for applying the substance transfer componentto the surface of the skin of the subject, e.g., so that fluid may bedelivered and/or received from the skin of the subject. In some cases,the support structure may immobilize the substance transfer componentsuch that the substance transfer component cannot move relative to thesupport structure; in other cases, however, the substance transfercomponent may be able to move relative to the support structure. In oneembodiment, as a non-limiting example, the substance transfer componentis immobilized relative to the support structure, and the supportstructure is positioned within the device such that application of thedevice to the skin causes at least a portion of the substance transfercomponent to pierce the skin of the subject.

In some embodiments, the deployment actuator, or a portion of thedeployment actuator, may move from a first position to a secondposition. For example, the first position may be one where thedeployment actuator has attached thereto a substance transfer componentthat is not in contact with the skin (e.g., a skin insertion object ofthe substance transfer component may be contained within a recess of thesubstance transfer component), while the second position of thedeployment actuator may be one where the substance transfer componentdoes contact the skin, e.g., to pierce the skin. The deployment actuatormay be moved using any suitable technique, e.g., manually, mechanically,electromagnetically, using a servo mechanism, or the like. In one set ofembodiments, for example, the deployment actuator may be moved from afirst position to a second position by pushing a button on the device,which causes the deployment actuator to move (either directly, orthrough a mechanism linking the button with the deployment actuator).Other mechanisms (e.g., dials, levers, sliders, etc., as discussedherein) may be used in conjunction of or instead of a button. In anotherset of embodiments, the deployment actuator may be moved from a firstposition to a second position automatically, for example, uponactivation by a computer, upon remote activation, after a period of timehas elapsed, or the like. For example, in one embodiment, a servoconnected to the deployment actuator is activated electronically, movingthe deployment actuator from the first position to the second position.In some cases, the deployment actuator may include a triggeringmechanism that initiates deployment.

In some cases, the deployment actuator and/or the substance transfercomponent may also be moved from the second position to the firstposition (or some other position). For example, after fluid has beendelivered and/or received from the skin, e.g., using a substancetransfer component, the deployment actuator may be moved, which may movethe substance transfer component away from contact with the skin. Thedeployment actuator may be moved from the second position to the firstposition using any suitable technique, including those described above,and the technique for moving the deployment actuator from the secondposition to the first position may be the same or different as thatmoving the deployment actuator from the first position to the secondposition.

In some cases, the device may be able to draw skin towards the substancetransfer component. For example, in one set of embodiments, the devicemay include a vacuum interface or region. The interface or region may beconnected with a vacuum source (external and/or internal to the device),and when a vacuum is applied, skin may be drawn towards the device,e.g., for contact with a substance transfer component, such as one ormore needles or microneedles.

In certain embodiments, the may also include a device actuator. Thedevice actuator may be constructed and arranged to cause exposure of thesubstance transfer component to the skin upon actuation of the deviceactuator. For example, the activator may cause the substance transfercomponent to release a chemical to contact the skin, a microneedle orother substance transfer component to be driven into the skin, a vacuumto be applied to the skin, a jet of fluid to be directed to the skin, orthe like. The device actuator may be actuated by the subject, and/or byanother person (e.g., a health care provider), or the device itself maybe self-actuating, e.g., upon application to the skin of a subject. Theactuator may be actuated once, or multiple times in some cases.

The device may be activated, for example, by pushing a button, pressinga switch, moving a slider, turning a dial, or the like. The subject,and/or another person, may activate the device activator. In some cases,the device may be remotely activated. For example, a health careprovider may send an electromagnetic signal which is received by thedevice in order to activate the device, e.g., a wireless signal, aBluetooth signal, an Internet signal, a radio signal, etc.

In one set of embodiments, the device may include channels such asmicrofluidic channels, which may be used to deliver and/or receivefluids and/or other materials into or out of the skin. In some cases,the microfluidic channels are in fluid communication with a substancetransfer component that is used to deliver and/or receive fluids to orfrom the skin. For example, in one set of embodiments, the device mayinclude a hypodermic needle that can be inserted into the skin, andfluid may be delivered into the skin via the needle and/or received fromthe skin via the needle. The device may also include one or moremicrofluidic channels to contain fluid for delivery to the needle, e.g.,from a source of fluid, and/or to receive fluid from the skin, e.g., fordelivery to an analytical chamber within the device, to a reservoir forlater analysis, or the like.

In some cases, more than one chamber may be present within the device,and in some cases, some or all of the chambers may be in fluidiccommunication, e.g., via channels such as microfluidic channels. Invarious embodiments, a variety of chambers and/or channels may bepresent within the device, depending on the application. For example,the device may contain chambers for sensing an analyte, chambers forholding reagents, chambers for controlling temperature, chambers forcontrolling pH or other conditions, chambers for creating or bufferingpressure or vacuum, chambers for controlling or dampening fluid flow,mixing chambers, or the like.

Thus, in one set of embodiments, the device may include a microfluidicchannel. As used herein, “microfluidic,” “microscopic,” “microscale,”the “micro-” prefix (for example, as in “microchannel”), and the likegenerally refers to elements or articles having widths or diameters ofless than about 1 mm, and less than about 100 microns (micrometers) insome cases. In some embodiments, larger channels may be used instead of,or in conjunction with, microfluidic channels for any of the embodimentsdiscussed herein. For example, channels having widths or diameters ofless than about 10 mm, less than about 9 mm, less than about 8 mm, lessthan about 7 mm, less than about 6 mm, less than about 5 mm, less thanabout 4 mm, less than about 3 mm, or less than about 2 mm may be used incertain instances. In some cases, the element or article includes achannel through which a fluid can flow. In all embodiments, specifiedwidths can be a smallest width (i.e. a width as specified where, at thatlocation, the article can have a larger width in a different dimension),or a largest width (i.e. where, at that location, the article has awidth that is no wider than as specified, but can have a length that isgreater). Thus, for instance, the microfluidic channel may have anaverage cross-sectional dimension (e.g., perpendicular to the directionof flow of fluid in the microfluidic channel) of less than about 1 mm,less than about 500 microns, less than about 300 microns, or less thanabout 100 microns. In some cases, the microfluidic channel may have anaverage diameter of less than about 60 microns, less than about 50microns, less than about 40 microns, less than about 30 microns, lessthan about 25 microns, less than about 10 microns, less than about 5microns, less than about 3 microns, or less than about 1 micron.

A “channel,” as used herein, means a feature on or in an article (e.g.,a substrate) that at least partially directs the flow of a fluid. Insome cases, the channel may be formed, at least in part, by a singlecomponent, e.g. an etched substrate or molded unit. The channel can haveany cross-sectional shape, for example, circular, oval, triangular,irregular, square or rectangular (having any aspect ratio), or the like,and can be covered or uncovered (i.e., open to the external environmentsurrounding the channel). In embodiments where the channel is completelycovered, at least one portion of the channel can have a cross-sectionthat is completely enclosed, and/or the entire channel may be completelyenclosed along its entire length with the exception of its inlet andoutlet.

A channel may have any aspect ratio, e.g., an aspect ratio (length toaverage cross-sectional dimension) of at least about 2:1, more typicallyat least about 3:1, at least about 5:1, at least about 10:1, etc. Asused herein, a “cross-sectional dimension,” in reference to a fluidic ormicrofluidic channel, is measured in a direction generally perpendicularto fluid flow within the channel. A channel generally will includecharacteristics that facilitate control over fluid transport, e.g.,structural characteristics and/or physical or chemical characteristics(hydrophobicity vs. hydrophilicity) and/or other characteristics thatcan exert a force (e.g., a containing force) on a fluid. The fluidwithin the channel may partially or completely fill the channel. In somecases the fluid may be held or confined within the channel or a portionof the channel in some fashion, for example, using surface tension(e.g., such that the fluid is held within the channel within a meniscus,such as a concave or convex meniscus). In an article or substrate, some(or all) of the channels may be of a particular size or less, forexample, having a largest dimension perpendicular to fluid flow of lessthan about 5 mm, less than about 2 mm, less than about 1 mm, less thanabout 500 microns, less than about 200 microns, less than about 100microns, less than about 60 microns, less than about 50 microns, lessthan about 40 microns, less than about 30 microns, less than about 25microns, less than about 10 microns, less than about 3 microns, lessthan about 1 micron, less than about 300 nm, less than about 100 nm,less than about 30 nm, or less than about 10 nm or less in some cases.In one embodiment, the channel is a capillary.

A variety of materials and methods, according to certain aspects of theinvention, can be used to form the device, e.g., microfluidic channels,chambers, etc. For example, various components of the invention can beformed from solid materials, in which the channels can be formed viamicromachining, film deposition processes such as spin coating andchemical vapor deposition, laser fabrication, photolithographictechniques, etching methods including wet chemical or plasma processes,and the like. See, for example, Scientific American, 248:44-55, 1983(Angell, et al).

In one set of embodiments, various components of the systems and devicesof the invention can be formed of a polymer, for example, an elastomericpolymer such as polydimethylsiloxane (“PDMS”), polytetrafluoroethylene(“PTFE” or Teflon®), or the like. For instance, according to oneembodiment, a microfluidic channel may be implemented by fabricating thefluidic system separately using PDMS or other soft lithographytechniques (details of soft lithography techniques suitable for thisembodiment are discussed in the references entitled “Soft Lithography,”by Younan Xia and George M. Whitesides, published in the Annual Reviewof Material Science, 1998, Vol. 28, pages 153-184, and “Soft Lithographyin Biology and Biochemistry,” by George M. Whitesides, Emanuele Ostuni,Shuichi Takayama, Xingyu Jiang and Donald E. Ingber, published in theAnnual Review of Biomedical Engineering, 2001, Vol. 3, pages 335-373;each of these references is incorporated herein by reference).

Other examples of potentially suitable polymers include, but are notlimited to, polyethylene terephthalate (PET), polyacrylate,polymethacrylate, polycarbonate, polystyrene, polyethylene,polypropylene, polyvinylchloride, cyclic olefin copolymer (COC),polytetrafluoroethylene, a fluorinated polymer, a silicone such aspolydimethylsiloxane, polyvinylidene chloride, bis-benzocyclobutene(“BCB”), a polyimide, a fluorinated derivative of a polyimide, or thelike. Combinations, copolymers, or blends involving polymers includingthose described above are also envisioned. The device may also be formedfrom composite materials, for example, a composite of a polymer and asemiconductor material.

In some embodiments, various components of the invention are fabricatedfrom polymeric and/or flexible and/or elastomeric materials, and can beconveniently formed of a hardenable fluid, facilitating fabrication viamolding (e.g. replica molding, injection molding, cast molding, etc.).The hardenable fluid can be essentially any fluid that can be induced tosolidify, or that spontaneously solidifies, into a solid capable ofcontaining and/or transporting fluids contemplated for use in and withthe fluidic network. In one embodiment, the hardenable fluid comprises apolymeric liquid or a liquid polymeric precursor (i.e. a “prepolymer”).Suitable polymeric liquids can include, for example, thermoplasticpolymers, thermoset polymers, waxes, metals, or mixtures or compositesthereof heated above their melting point. As another example, a suitablepolymeric liquid may include a solution of one or more polymers in asuitable solvent, which solution forms a solid polymeric material uponremoval of the solvent, for example, by evaporation. Such polymericmaterials, which can be solidified from, for example, a melt state or bysolvent evaporation, are well known to those of ordinary skill in theart. A variety of polymeric materials, many of which are elastomeric,are suitable, and are also suitable for forming molds or mold masters,for embodiments where one or both of the mold masters is composed of anelastomeric material. A non-limiting list of examples of such polymersincludes polymers of the general classes of silicone polymers, epoxypolymers, and acrylate polymers. Epoxy polymers are characterized by thepresence of a three-membered cyclic ether group commonly referred to asan epoxy group, 1,2-epoxide, or oxirane. For example, diglycidyl ethersof bisphenol A can be used, in addition to compounds based on aromaticamine, triazine, and cycloaliphatic backbones. Another example includesthe well-known Novolac polymers. Non-limiting examples of siliconeelastomers suitable for use according to the invention include thoseformed from precursors including the chlorosilanes such asmethylchlorosilanes, ethylchlorosilanes, phenylchlorosilanes, etc.

Silicone polymers are used in certain embodiments, for example, thesilicone elastomer polydimethylsiloxane. Non-limiting examples of PDMSpolymers include those sold under the trademark Sylgard by Dow ChemicalCo., Midland, Mich., and particularly Sylgard 182, Sylgard 184, andSylgard 186. Silicone polymers including PDMS have several beneficialproperties simplifying fabrication of the microfluidic structures of theinvention. For instance, such materials are inexpensive, readilyavailable, and can be solidified from a prepolymeric liquid via curingwith heat. For example, PDMSs are typically curable by exposure of theprepolymeric liquid to temperatures of about, for example, about 65° C.to about 75° C. for exposure times of, for example, about an hour. Also,silicone polymers, such as PDMS, can be elastomeric and thus may beuseful for forming very small features with relatively high aspectratios, necessary in certain embodiments of the invention. Flexible(e.g., elastomeric) molds or masters can be advantageous in this regard.

One advantage of forming structures such as microfluidic structures ofthe invention from silicone polymers, such as PDMS, is the ability ofsuch polymers to be oxidized, for example by exposure to anoxygen-containing plasma such as an air plasma, so that the oxidizedstructures contain, at their surface, chemical groups capable ofcross-linking to other oxidized silicone polymer surfaces or to theoxidized surfaces of a variety of other polymeric and non-polymericmaterials. Thus, components can be fabricated and then oxidized andessentially irreversibly sealed to other silicone polymer surfaces, orto the surfaces of other substrates reactive with the oxidized siliconepolymer surfaces, without the need for separate adhesives or othersealing means. In most cases, sealing can be completed simply bycontacting an oxidized silicone surface to another surface without theneed to apply auxiliary pressure to form the seal. That is, thepre-oxidized silicone surface acts as a contact adhesive againstsuitable mating surfaces. Specifically, in addition to beingirreversibly sealable to itself, oxidized silicone such as oxidized PDMScan also be sealed irreversibly to a range of oxidized materials otherthan itself including, for example, glass, silicon, silicon oxide,quartz, silicon nitride, polyethylene, polystyrene, glassy carbon, andepoxy polymers, which have been oxidized in a similar fashion to thePDMS surface (for example, via exposure to an oxygen-containing plasma).Oxidation and sealing methods useful in the context of the presentinvention, as well as overall molding techniques, are described in theart, for example, in an article entitled “Rapid Prototyping ofMicrofluidic Systems and Polydimethylsiloxane,” Anal. Chem., 70:474-480,1998 (Duffy et al.), incorporated herein by reference.

In some embodiments, the device may include a sensor, for exampleembedded within or integrally connected to the device, or positionedremotely but with physical, electrical, and/or optical connection withthe device so as to be able to sense a compartment within the device.For example, the sensor may be in fluidic communication with fluidreceived from a subject, directly, via a microfluidic channel, ananalytical chamber, etc. The sensor may be able to sense an analyte,e.g., one that is suspected of being in a fluid received from a subject.For example, a sensor may be free of any physical connection with thedevice, but may be positioned so as to detect the results of interactionof electromagnetic radiation, such as infrared, ultraviolet, or visiblelight, which has been directed toward a portion of the device, e.g., achamber within the device. As another example, a sensor may bepositioned on or within the device, and may sense activity in a chamberby being connected optically to the chamber. Sensing communication canalso be provided where the chamber is in communication with a sensorfluidly, optically or visually, thermally, pneumatically,electronically, or the like, so as to be able to sense a condition ofthe chamber. As one example, the sensor may be positioned downstream ofa chamber, within a channel such a microfluidic channel, on an externalapparatus, or the like.

The sensor may be, for example, a pH sensor, an optical sensor, anoxygen sensor, a sensor able to detect the concentration of a substance,or the like. Non-limiting examples of sensors include dye-baseddetection systems, affinity-based detection systems, microfabricatedgravimetric analyzers, CCD cameras, optical detectors, opticalmicroscopy systems, electrical systems, thermocouples and thermistors,pressure sensors, etc. Those of ordinary skill in the art will be ableto identify other suitable sensors. The sensor can include acolorimetric detection system in some cases, which may be external tothe device, or microfabricated into the device in certain cases. As anexample of a colorimetric detection system, if a dye or a fluorescententity is used (e.g. in a particle), the colorimetric detection systemmay be able to detect a change or shift in the frequency and/orintensity of the dye or fluorescent entity.

Examples of analytes that the sensor may be used to determine include,but are not limited to, pH or metal ions, proteins, nucleic acids (e.g.DNA, RNA, etc.), drugs, sugars (e.g., glucose), hormones (e.g.,estradiol, estrone, progesterone, progestin, testosterone,androstenedione, etc.), carbohydrates, or other analytes of interest.Other conditions that can be determined can include pH changes, whichmay indicate disease, yeast infection, periodontal disease at a mucosalsurface, oxygen or carbon monoxide levels which indicate lungdysfunction, and drug levels, e.g., legal prescription levels of drugssuch as coumadin, other drugs such as nicotine, or illegal such ascocaine. Further examples of analytes include those indicative ofdisease, such as cancer specific markers such as CEA and PSA, viral andbacterial antigens, and autoimmune indicators such as antibodies todouble stranded DNA, indicative of Lupus. Still other conditions includeexposure to elevated carbon monoxide, which could be from an externalsource or due to sleep apnea, too much heat (important in the case ofbabies whose internal temperature controls are not fullyself-regulating) or from fever. Still other potentially suitableanalytes include various pathogens such as bacteria or viruses, and/ormarkers produced by such pathogens.

As additional non-limiting examples, the sensor may contain an antibodyable to interact with a marker for a disease state, an enzyme such asglucose oxidase or glucose 1-dehydrogenase able to detect glucose, orthe like. The analyte may be determined quantitatively or qualitatively,and/or the presence or absence of the analyte within the received fluidmay be determined in some cases. Those of ordinary skill in the art willbe aware of many suitable commercially-available sensors, and thespecific sensor used may depend on the particular analyte being sensed.

Still other potentially suitable analytes include various pathogens suchas bacteria or viruses, and/or markers produced by such pathogens. Thus,in certain embodiments of the invention, as discussed below, one or moreanalytes within the pooled region of fluid may be determined in somefashion, which may be useful in determining a past, present and/orfuture condition of the subject.

In one embodiment as discussed below, an analyte may be determined as an“on/off” or “normal/abnormal” situation. Detection of the analyte, forexample, may be indicative that insulin is needed; a trip to the doctorto check cholesterol; ovulation is occurring; kidney dialysis is needed;drug levels are present (e.g., especially in the case of illegal drugs)or too high/too low (e.g., important in care of geriatrics in particularin nursing homes). As another embodiment, however, an analyte may bedetermined quantitatively.

As described herein, any of a variety of signaling or display methods,associated with analyses, can be provided including signaling visually,by smell, sound, feel, taste, or the like, in some embodiments. Signalstructures include, but are not limited to, displays (visual, LED,light, etc.), speakers, chemical-releasing compartments (e.g.,containing a volatile chemical), mechanical devices, heaters, coolers,or the like. In some cases, the signal structure may be integral withthe device (e.g., integrally connected with a support structure forapplication to the skin of the subject, e.g., containing a substancetransfer component such as a microneedle), or the signal structure maynot be integrally connected with the support structure.

In some embodiments, signaling methods such as these may be used toindicate the presence and/or concentration of an analyte determined bythe sensor, e.g., to the subject, and/or to another entity, such asthose described below. Where a visual signal is provided, it can beprovided in the form of change in opaqueness, a change in intensity ofcolor and/or opaqueness, or can be in the form of a message (e.g.,numerical signal, or the like), an icon (e.g., signaling by shape orotherwise a particular medical condition), a brand, logo, or the like.For instance, in one embodiment, the device may include a display. Awritten message such as “take next dose,” or “glucose level is high” ora numerical value might be provided, or a message such as “toxin ispresent.” These messages, icons, logos, or the like can be provided asan electronic read-out by a component of a device and/or can bedisplayed as in inherent arrangement of one or more components of thedevice.

In some embodiments, a device is provided where the device determines aphysical condition of a subject and produces a signal related to thecondition that can be readily understood by the subject (e.g., byprovision of a visual “OK” signal as described above) or can be designedso as not to be readily understandable by a subject. Where not readilyunderstandable, the signal can take a variety of forms. In one form, thesignal might be a series of letters or numbers that mean nothing to thesubject (e.g., A1278CDQ) which would have meaning to a medicalprofessional or the like (and/or be decodable by the same, e.g., withreference to a suitable decoder) and can be associated with a particularphysiological condition. Alternatively, a signal in the form of bar codecan be provided by a device such that, under a particular condition orset of conditions the bar code appears and/or disappears, or changes,and can be read by a bar code reader to communicate information aboutthe subject or analyte. In another embodiment, the device can bedesigned such that an ultraviolet signal is produced, or a signal thatcan be read only under ultraviolet light (e.g., a simple spot or patch,or any other signal such as a series of number, letters, bar code,message, or the like that can be readily understandable or not readilyunderstandable by a subject) can be provided. The signal may beinvisible to the human eye but, upon application UV light or otherexcitation energy, may be readable. The signal can be easily readable orunderstandable by a user via visual observation, or with other sensoryactivity such smell, feel, etc. In certain embodiments, equipment asdescribed above may be needed to determine a signal provided by thedevice, such as equipment in a clinical setting, etc. In some cases, thedevice is able to transmit a signal indicative of the analyte to areceiver, e.g., as a wireless signal, a Bluetooth signal, an Internetsignal, a radio signal, etc.

In some embodiments, quantitative and/or qualitative analyses can beprovided by a device. That is, the device in some cases may provideanalyses that allow “yes/no” tests or the like, or tests that provideinformation on the quantity, concentration, or level of a particularanalyte or analytes. Display configurations can be provided by theinvention that reflect the amount of a particular analyte present in asubject at a particular point in time, or any other variable (presenceof analysis over time, type of analyte, etc.) display configurations cantake a variety of forms. In one example, a dial can be provided, similarto that of a speedometer with a series of level indications (e.g.,numbers around the dial) and a “needle” or other device that indicates aparticular level. In other configurations, a particular area of thedevice (e.g., on a display) can exist that is filled in to a greater orlesser extent depending upon the presence and/or quantity of aparticular analyte present, e.g., in the form of a bar graph. In anotherarrangement a “color wheel” can be provided where the amount of aparticular analyte present can control which colors of the wheel arevisible. Or, different analytes can cause different colors of a wheel ordifferent bars of a graph to become visible or invisible in a multipleanalyte analysis. Multiple-analyte quantitative analyses can bereflected in multiple color wheels, a single color wheel with differentcolors per analyte where the intensity of each color reflects the amountof the analyte, or, for example, a plurality of bar graphs where eachbar graph is reflective of a particular analyte and the level of the bar(and/or degree to which an area is filled in with visible color or othervisible feature) is reflective of the amount of the analyte. As with allembodiments here, whatever signal is displayed can be understandable ornot understandable to any number of participants. For example, it can beunderstandable to a subject or not understandable to a subject. Wherenot understandable it might need to be decoded, read electronically, orthe like. Where read electronically, for example, a device may provide asignal that is not understandable to a subject or not even visible orotherwise able to be sensed by a subject, and a reader can be providedadjacent or approximate the device that can provide a visible signalthat is understandable or not understandable to the subject, or cantransmit a signal to another entity for analysis.

In connection with any signals associated with any analyses describedherein, another, potentially related signal or other display (or smell,taste, or the like) can be provided which can assist in interpretingand/or evaluating the signal. In one arrangement, a calibration orcontrol is provided proximate (or otherwise easily comparable with) asignal, e.g., a visual calibration/control or comparator next to orclose to a visual signal provided by a device and/or implanted agents,particles, or the like.

A visual control or reference can be used with another sensory signal,such as that of smell, taste, temperature, itch, etc. Areference/control and/or experimental confirmation component can beprovided, to be used in connection with an in-skin test or vice versa.References/indicators can also be used to indicate the state of life ofa device, changing color or intensity and/or changing in anothersignaling aspect as the device changes relative to its useful life, sothat a user can determine when the device should no longer be reliedupon and/or removed. For certain devices, an indicator or control can beaffected by adding analyte to the control (e.g., from a source outsideof the source to be determine) to confirm operability of the deviceand/or to provide a reference against which to measure a signal of thedevice. For example, a device can include a button to be tapped by auser which will allow an analyte from a reservoir to transfer to anindicator region to provide a signal, to demonstrate operability of thedevice and/or provide a comparator for analysis.

Many of the embodiments described herein involve a quantitative analysisand related signal, i.e., the ability to determine the relative amountor concentration of an analyte in a medium. This can be accomplished ina variety of ways. For example, where an agent (e.g. a binding partnerattached to a nanoparticle) is used to capture and analyze an analyte,the agent can be provided in a gradient in concentration across asensing region of the device. Or a sensing region can include a membraneor other apparatus through which analyte is required to flow or passprior to capture and identification, and the pathway for analyte travelcan vary as a function of position of display region. For example, amembrane can be provided across a sensing region, through which analytemust pass prior to interacting with a layer of binding and/or signalingagent, and the membrane may vary in thickness laterally in a directionrelated to “bar graph” readout. Where a small amount of analyte ispresent, it may pass through the thinner portion but not the thickerportion of the membrane, but where a larger amount is present, it maypass across a thicker portion. The boundary (where one exists) between aregion through which analyte passes, and one through which it does notcompletely pass, can define the “line” of the bar graph. Other ways ofachieving the same or a similar result can include varying theconcentration of a scavenger or transporter of the analyte, or anintermediate reactive species (between analyte and signaling event),across a membrane or other article, gradient in porosity or selectivityof the membrane, ability to absorb or transport sample fluid, or thelike. These principles, in combination with other disclosure herein, canbe used to facilitate any or all of the quantitative analyses describedherein.

In certain embodiments, a subject having a condition such as aphysiological condition to be analyzed (or other user, such as medicalpersonnel) reads and/or otherwise determines a signal from a device. Forexample, the device may transmit a signal indicative of a condition ofthe subject and/or the device. Alternatively, or in addition, a signalproduced by a device can be acquired in the form of a representation(e.g. a digitized signal, or the like) and transmitted to another entityfor analysis and/or action. For example, a signal can be produced by adevice, e.g., based on a sensor reading of an analyte, based on fluiddelivered and/or received from the skin, based on a condition of thedevice, or the like. The signal may represent any suitable data orimage. For example, the signal may represent the presence and/orconcentration of an analyte in fluid received from a subject, the amountof fluid received from a subject and/or delivered to the subject, thenumber of times the device has been used, the battery life of thedevice, the amount of vacuum left in the device, the cleanliness orsterility of the device, the identity of the device (e.g., wheremultiple devices are given unique identification numbers, to preventcounterfeiting, accidental exchange of equipment to incorrect users,etc.), or the like. For instance, in some embodiments, an image of thesignal (e.g., a visual image or photograph) can be obtained andtransmitted to a different entity (for example, a user can take a cellphone picture of a signal generated by the device and send it, via cellphone, the other entity).

The other entity that the signal is transmitted to can be a human (e.g.,a clinician) or a machine. In some cases, the other entity may be ableto analyze the signal and take appropriate action. In one arrangement,the other entity is a machine or processor that analyzes the signal andoptionally sends a signal back to the device to give direction as toactivity (e.g., a cell phone can be used to transmit an image of asignal to a processor which, under one set of conditions, transmits asignal back to the same cell phone giving direction to the user, ortakes other action). Other actions can include automatic stimulation ofthe device or a related device to dispense a medicament orpharmaceutical, or the like. The signal to direct dispensing of apharmaceutical can take place via the same used to transmit the signalto the entity (e.g., cell phone) or a different vehicle or pathway.Telephone transmission lines, wireless networks, Internet communication,and the like can also facilitate communication of this type.

As one specific example, a device may be a glucose monitor. As signalmay be generated by the device and an image of the signal captured by acell phone camera and then transmitted via cell phone to a clinician.The clinician may then determine that the glucose (or e.g., insulin)level is appropriate or inappropriate and send a message indicating thisback to the subject via cell phone.

Information regarding the analysis can also be transmitted to the sameor a different entity, or a different location simply by removing thedevice or a portion of the device from the subject and transferring itto a different location. For example, a device can be used in connectionwith a subject to analyze presence and/or amount of a particularanalyte. At some point after the onset of use, the device, or a portionof the device carrying a signal or signals indicative of the analysis oranalyses, can be removed and, e.g., attached to a record associated withthe subject. As a specific example, a patch can be worn by a subject todetermine presence and/or amount of one or more analytes qualitatively,quantitatively, and/or over time. The subject can visit a clinician whocan remove the patch or a portion of the patch and attach it to amedical record associated with the subject.

According to various sets of embodiments, the device may be used one, ormultiple times, depending on the application. For instance, obtainingsamples for sensing, according to certain embodiments of the invention,can be done such that sensing can be carried out continuously,discretely, or a combination of these. For example, where a bodily fluidsuch as interstitial fluid is accessed for determination of an analyte,fluid can be accessed discretely (i.e., as a single dose, once ormultiple times), or continuously by creating a continuous flow of fluidwhich can be analyzed once or any number of times. Additionally, testingcan be carried out once, at a single point in time, or at multiplepoints in time, and/or from multiple samples (e.g., at multiplelocations relative to the subject).

Alternatively or in addition, testing can be carried out continuouslyover any number of points in time involving one or any number oflocations relative to the subject or other multiple samples. As anexample, one bolus or isolated sample, of fluid such as interstitialfluid can be obtained. From that fluid a test can be carried out todetermine whether a particular analyte or other agent exists in thefluid. Alternatively, two or more tests can be carried out involvingthat quantity of fluid to determine the presence and/or quantity of twoor more analytes, and any number of such tests can be carried out. Testsinvolving that quantity of fluid can be carried out simultaneously orover a period of time. For example, a test for a particular analyte canbe carried out at various points in time to determine whether the resultchanges over time, or different analytes can be determined at differentpoints in time. As another example, a pool of fluid can be formedbetween layers of skin via, e.g., a suction blister and either withinthe suction blister or from fluid drawn from the suction blister andplaced elsewhere, any of the above and other analysis can be carried outat one or more points in time. Where a suction blister is formed in sucha way that interstitial fluid within the blister changes over time(where an equilibrium exists between interstitial fluid within thesubject and interstitial fluid in the suction blister itself, i.e., thefluid within the blister is ever changing to reflect the content of theinterstitial fluid of the subject in the region of the blister overtime). Testing of fluid within or from the suction blister at variouspoints in time can provide useful information.

In another example, a microneedle or microneedles, or other device(s)can be used to access a fluid of a subject such as interstitial fluid orblood. Fluid can be drawn to a point of analysis and analyzed in anymanner described herein. For example, an analysis can be carried outonce, to determine the presence and/or quantity of a single analyte, ora number of tests can be carried out. From a single sample of fluid, aparticular test or number of tests can be carried out essentiallysimultaneously, or analyses can be carried out over time. Moreover,fluid can be drawn continuously from the subject and one or more testscan be carried out of any number of points in time. A variety of reasonsfor carrying out one or more tests over the course of time exists, aswould be understood by those of ordinary skill in the art. One suchreason is to determine whether the quantity or another characteristic ofan analyte is constant in a subject, or changes over time. A variety ofspecific techniques for continuous and/or discrete testing will bedescribed herein.

Where microneedles are used, it can be advantageous to select needles oflength such that interstitial fluid is preferentially obtained and,where not desirable, blood is not accessed. Those of ordinary skill inthe art can arrange microneedles relative to the skin for these purposesincluding, in one embodiment, introducing microneedles into the skin atan angle, relative to the skin's surface, other than 90°, i.e., tointroduce a needle or needles into the skin in a slanting fashion so asto access interstitial fluid.

In another aspect, the present invention is directed to a kit includingone or more of the compositions previously discussed, e.g., a kitincluding a device for the delivery and/or receiving of fluid from theskin, a kit including a device able to determine a fluid, a kitincluding a drug and a device able to determine the drug within theskin, or the like. A “kit,” as used herein, typically defines a packageor an assembly including one or more of the compositions of theinvention, and/or other compositions associated with the invention, forexample, as previously described. Each of the compositions of the kitmay be provided in liquid form (e.g., in solution), or in solid form(e.g., a dried powder). In certain cases, some of the compositions maybe constitutable or otherwise processable (e.g., to an active form), forexample, by the addition of a suitable solvent or other species, whichmay or may not be provided with the kit. Examples of other compositionsor components associated with the invention include, but are not limitedto, solvents, surfactants, diluents, salts, buffers, emulsifiers,chelating agents, fillers, antioxidants, binding agents, bulking agents,preservatives, drying agents, antimicrobials, needles, syringes,packaging materials, tubes, bottles, flasks, beakers, dishes, frits,filters, rings, clamps, wraps, patches, containers, tapes, adhesives,and the like, for example, for using, administering, modifying,assembling, storing, packaging, preparing, mixing, diluting, and/orpreserving the compositions components for a particular use, forexample, to a sample and/or a subject.

A kit of the invention may, in some cases, include instructions in anyform that are provided in connection with the compositions of theinvention in such a manner that one of ordinary skill in the art wouldrecognize that the instructions are to be associated with thecompositions of the invention. For instance, the instructions mayinclude instructions for the use, modification, mixing, diluting,preserving, administering, assembly, storage, packaging, and/orpreparation of the compositions and/or other compositions associatedwith the kit. In some cases, the instructions may also includeinstructions for the delivery and/or administration of the compositions,for example, for a particular use, e.g., to a sample and/or a subject.The instructions may be provided in any form recognizable by one ofordinary skill in the art as a suitable vehicle for containing suchinstructions, for example, written or published, verbal, audible (e.g.,telephonic), digital, optical, visual (e.g., videotape, DVD, etc.) orelectronic communications (including Internet or web-basedcommunications), provided in any manner.

In some embodiments, the present invention is directed to methods ofpromoting one or more embodiments of the invention as discussed herein.As used herein, “promoted” includes all methods of doing businessincluding, but not limited to, methods of selling, advertising,assigning, licensing, contracting, instructing, educating, researching,importing, exporting, negotiating, financing, loaning, trading, vending,reselling, distributing, repairing, replacing, insuring, suing,patenting, or the like that are associated with the systems, devices,apparatuses, articles, methods, compositions, kits, etc. of theinvention as discussed herein. Methods of promotion can be performed byany party including, but not limited to, personal parties, businesses(public or private), partnerships, corporations, trusts, contractual orsub-contractual agencies, educational institutions such as colleges anduniversities, research institutions, hospitals or other clinicalinstitutions, governmental agencies, etc. Promotional activities mayinclude communications of any form (e.g., written, oral, and/orelectronic communications, such as, but not limited to, e-mail,telephonic, Internet, Web-based, etc.) that are clearly associated withthe invention.

In some embodiments, the method of promotion may involve one or moreinstructions. As used herein, “instructions” can define a component ofinstructional utility (e.g., directions, guides, warnings, labels,notes, FAQs or “frequently asked questions,” etc.), and typicallyinvolve written instructions on or associated with the invention and/orwith the packaging of the invention. Instructions can also includeinstructional communications in any form (e.g., oral, electronic,audible, digital, optical, visual, etc.), provided in any manner suchthat a user will clearly recognize that the instructions are to beassociated with the invention, e.g., as discussed herein.

The following documents are incorporated herein by reference: U.S.Provisional Patent Application Ser. No. 61/058,796, filed Jun. 4, 2008,entitled “Compositions and Methods for Diagnostics, Therapies, and OtherApplications”; U.S. Provisional Patent Application Ser. No. 61/163,791,filed Mar. 26, 2009, entitled “Composition and Methods for RapidOne-Step Diagnosis”; U.S. Provisional Patent Application Ser. No.61/163,793, filed Mar. 26, 2009, entitled “Compositions and Methods forDiagnostics, Therapies, and Other Applications”; U.S. patent applicationSer. No. 12/478,756, filed Jun. 4, 2009, entitled “Compositions andMethods for Diagnostics, Therapies, and Other Applications”;International Patent Application No. PCT/US09/046333, filed Jun. 4,2009, entitled “Compositions and Methods for Diagnostics, Therapies, andOther Applications”; U.S. Provisional Patent Application Ser. No.61/163,710, filed Mar. 26, 2009, entitled “Systems and Methods forCreating and Using Suction Blisters or Other Pooled Regions of Fluidwithin the Skin”; U.S. Provisional Patent Application Ser. No.61/163,733, filed Mar. 26, 2009, entitled “Determination of Tracerswithin Subjects”; U.S. Provisional Patent Application Ser. No.61/163,750, filed Mar. 26, 2009, entitled “Monitoring of Implants andOther Devices”; U.S. Provisional Patent Application Ser. No. 61/154,632,filed Mar. 2, 2009, entitled “Oxygen Sensor”; and U.S. ProvisionalPatent Application Ser. No. 61/269,436, filed Jun. 24, 2009, entitled“Devices and Techniques associated with Diagnostics, Therapies, andOther Applications, Including Skin-Associated Applications.” Alsoincorporated herein by reference in its entirety is U.S. ProvisionalPatent Application Ser. No. 61/373,757, filed Aug. 13, 2010, entitled“Systems and Techniques for Monitoring Subjects,” by Levinson, et al.

While several embodiments of the present invention have been describedand illustrated herein, those of ordinary skill in the art will readilyenvision a variety of other means and/or structures for performing thefunctions and/or obtaining the results and/or one or more of theadvantages described herein, and each of such variations and/ormodifications is deemed to be within the scope of the present invention.More generally, those skilled in the art will readily appreciate thatall parameters, dimensions, materials, and configurations describedherein are meant to be exemplary and that the actual parameters,dimensions, materials, and/or configurations will depend upon thespecific application or applications for which the teachings of thepresent invention is/are used. Those skilled in the art will recognize,or be able to ascertain using no more than routine experimentation, manyequivalents to the specific embodiments of the invention describedherein. It is, therefore, to be understood that the foregoingembodiments are presented by way of example only and that, within thescope of the appended claims and equivalents thereto, the invention maybe practiced otherwise than as specifically described and claimed. Thepresent invention is directed to each individual feature, system,article, material, kit, and/or method described herein. In addition, anycombination of two or more such features, systems, articles, materials,kits, and/or methods, if such features, systems, articles, materials,kits, and/or methods are not mutually inconsistent, is included withinthe scope of the present invention.

All definitions, as defined and used herein, should be understood tocontrol over dictionary definitions, definitions in documentsincorporated by reference, and/or ordinary meanings of the definedterms.

The indefinite articles “a” and “an,” as used herein in thespecification and in the claims, unless clearly indicated to thecontrary, should be understood to mean “at least one.”

The phrase “and/or,” as used herein in the specification and in theclaims, should be understood to mean “either or both” of the elements soconjoined, i.e., elements that are conjunctively present in some casesand disjunctively present in other cases. Multiple elements listed with“and/or” should be construed in the same fashion, i.e., “one or more” ofthe elements so conjoined. Other elements may optionally be presentother than the elements specifically identified by the “and/or” clause,whether related or unrelated to those elements specifically identified.Thus, as a non-limiting example, a reference to “A and/or B”, when usedin conjunction with open-ended language such as “comprising” can refer,in one embodiment, to A only (optionally including elements other thanB); in another embodiment, to B only (optionally including elementsother than A); in yet another embodiment, to both A and B (optionallyincluding other elements); etc.

As used herein in the specification and in the claims, “or” should beunderstood to have the same meaning as “and/or” as defined above. Forexample, when separating items in a list, “or” or “and/or” shall beinterpreted as being inclusive, i.e., the inclusion of at least one, butalso including more than one, of a number or list of elements, and,optionally, additional unlisted items. Only terms clearly indicated tothe contrary, such as “only one of” or “exactly one of,” or, when usedin the claims, “consisting of,” will refer to the inclusion of exactlyone element of a number or list of elements. In general, the term “or”as used herein shall only be interpreted as indicating exclusivealternatives (i.e. “one or the other but not both”) when preceded byterms of exclusivity, such as “either,” “one of,” “only one of,” or“exactly one of.” “Consisting essentially of,” when used in the claims,shall have its ordinary meaning as used in the field of patent law.

As used herein in the specification and in the claims, the phrase “atleast one,” in reference to a list of one or more elements, should beunderstood to mean at least one element selected from any one or more ofthe elements in the list of elements, but not necessarily including atleast one of each and every element specifically listed within the listof elements and not excluding any combinations of elements in the listof elements. This definition also allows that elements may optionally bepresent other than the elements specifically identified within the listof elements to which the phrase “at least one” refers, whether relatedor unrelated to those elements specifically identified. Thus, as anon-limiting example, “at least one of A and B” (or, equivalently, “atleast one of A or B,” or, equivalently “at least one of A and/or B”) canrefer, in one embodiment, to at least one, optionally including morethan one, A, with no B present (and optionally including elements otherthan B); in another embodiment, to at least one, optionally includingmore than one, B, with no A present (and optionally including elementsother than A); in yet another embodiment, to at least one, optionallyincluding more than one, A, and at least one, optionally including morethan one, B (and optionally including other elements); etc.

It should also be understood that, unless clearly indicated to thecontrary, in any methods claimed herein that include more than one stepor act, the order of the steps or acts of the method is not necessarilylimited to the order in which the steps or acts of the method arerecited.

In the claims, as well as in the specification above, all transitionalphrases such as “comprising,” “including,” “carrying,” “having,”“containing,” “involving,” “holding,” “composed of,” and the like are tobe understood to be open-ended, i.e., to mean including but not limitedto. Only the transitional phrases “consisting of” and “consistingessentially of” shall be closed or semi-closed transitional phrases,respectively, as set forth in the United States Patent Office Manual ofPatent Examining Procedures, Section 2111.03.

What is claimed is: 1-57. (canceled)
 58. A device for application to askin of a subject for treating the subject with a drug, the devicecomprising: a substance transfer component comprising one or moremicroneedles; a deployment actuator configured and arranged to move froma first position to a second position and from the second position tothe first position, wherein when the deployment actuator is in the firstposition, the one or more microneedles do not contact the skin of thesubject, and wherein when the deployment actuator is in the secondposition, at least one of the microneedles pierce the skin of thesubject; a vacuum source able to create an internal pressure less thanatmospheric pressure; a sensing chamber, positioned within the device,for containing the blood withdrawn from the subject, wherein the sensingchamber is separate from the vacuum source, and wherein the vacuumsource is able to apply a vacuum to withdraw blood from the subject tobe contained by the sensing chamber after the microneedles pierces theskin of the subject; a sensor positioned in sensing communication withthe sensing chamber, the sensor being configured and arranged todetermine an analyte suspected of being present within the blood withinthe sensing chamber; a microprocessor positioned in electricalcommunication with the sensor; and a drug reservoir within the devicefor containing the drug deliverable to the subject, wherein the deviceis configured to deliver the drug from the reservoir to the skin of thesubject after the deployment actuator has moved from the first positionto the second position and from the second position to the firstposition.
 59. The device of claim 58, wherein the drug is deliverable tothe subject from the drug reservoir via the substance transfercomponent.
 60. The device of claim 58, wherein the device comprises asecond substance transfer component for delivering the drug from thedrug reservoir.
 61. The device of claim 60, wherein the second substancetransfer component comprises a needle.
 62. The device of claim 58, thedevice further comprising a reaction entity contained within the sensingchamber able to react with the analyte suspected of being present withinthe blood.
 63. The device of claim 58, the device further comprising asecond actuator that, when actuated, fluidly communicates the pressureless than atmospheric pressure in the vacuum source to a site ofpiercing of the microneedles with the skin of the subject.
 64. A devicefor application to the skin of a subject for indicating a condition, thedevice comprising: a substance transfer component comprising one or moremicroneedles; a deployment actuator configured and arranged to move froma first position to a second position and from the second position tothe first position, wherein when the deployment actuator is in the firstposition, the one or more microneedles do not contact the skin of thesubject, and wherein when the deployment actuator is in the secondposition, at least some of the microneedles pierce the skin of thesubject; a sensing chamber, positioned within the device, for containingblood from the subject; a vacuum source, separate from the sensingchamber, amle to create an internal pressure less than atmosphericpressure, the vacuum source is able to apply a vacuum to withdraw bloodfrom the subject to be contained by the sensing chamber after themicroneedles pierces the skin of the subject; a sensor positioned insensing communication with the sensing chamber, the sensor beingconfigured and arranged to determine an analyte suspected of beingpresent within the blood within the sensing chamber; a microprocessorpositioned in electrical communication with the sensor; and a visualand/or audible indicator determinable by a subject, the indicatorpositioned within the device in electrical communication with themicroprocessor.
 65. The device of claim 64, wherein the indicatorcomprise a visual indicator.
 66. The device of claim 65, wherein thevisual indicator comprises a light.
 67. The device of claim 64, whereinthe indictor comprises an audible indicator.
 68. The device of claim 64,wherein the indicator indicates an external reward based ondetermination of the analyte by the microprocessor.
 69. The device ofclaim 64, the device further comprising a reaction entity containedwithin the sensing chamber able to react with the analyte containedwithin the blood.
 70. The device of claim 64, the device furthercomprising an actuator that, when actuated, fluidly communicates thepressure less than atmospheric pressure in the vacuum source to a siteof piercing of the microneedles with the skin of the subject.
 71. Adevice for application to the skin of a subject for determining ananalyte, the device comprising: a substance transfer componentcomprising one or more microneedles; a deployment actuator configuredand arranged to move from a first position to a second position and fromthe second position to the first position, wherein when the deploymentactuator is in the first position, the one or more microneedles do notcontact the skin of the subject, and wherein when the deploymentactuator is in the second position, at least some of the microneedlespierce the skin of the subject; a sensing chamber, positioned within thedevice, for containing blood from the subject; a vacuum source, separatefrom the sensing chamber, able to create an internal pressure less thanatmospheric pressure to withdraw blood from the subject to be containedby the sensing chamber after the microneedles pierces the skin of thesubject; a first sensor positioned in sensing communication with thesensing chamber, the sensor being configured and arranged to determinean analyte suspected of being present within the blood within thesensing chamber; a second sensor configured and arranged to determine alocation of the device; and a microprocessor positioned in electricalcommunication with the first sensor and the second sensor.
 72. Thedevice of claim 71, wherein the second sensor comprises a GlobalPositioning System (GPS) sensor.
 73. The device of claim 71, wherein themicroprocessor is configured and arranged to produce composite datacomprising analyte data from the first sensor and location data from thesecond sensor.
 74. The device of claim 73, wherein the device furthercomprises a data storage compartment for recording the composite data.75. The device of claim 73, wherein the device further comprises atransmitter for transmitting the composite data.
 76. The device of claim71, the device further comprising a reaction entity contained within thestorage chamber able to react with the analyte contained within theblood.
 77. The device of claim 71, the device further comprising anactuator that, when actuated, fluidly communicates the pressure lessthan atmospheric pressure in the vacuum source to a site of piercing ofthe microneedles with the skin of the subject.